Piperazine PDE4 inhibitors and uses thereof

ABSTRACT

The invention includes a compound of formula I: 
     
       
         
         
             
             
         
       
     
     wherein R 1 , X, Z, n, and m have any of the values described herein, as well as salts of such compounds, compositions comprising such compounds, and therapeutic methods that comprise the administration of such compounds. The compounds are inhibitors of PDE4 function and are useful for improving cognitive function in animals.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation application under 37 C.F.R. §1.53(b) of U.S.patent application Ser. No. 11/679,782, filed on Feb. 27, 2007 now U.S.Pat. No. 7,829,713, which claims priority under 35 U.S.C. §119(e) toU.S. Provisional Patent Application Nos. 60/777,291, filed on Feb. 28,2006, each of which are hereby expressly incorporated by reference intheir entireties.

BACKGROUND OF INVENTION

An estimated 4 to 5 million Americans (about 2% of all ages and 15% ofthose older than 65) have some form and degree of cognitive failure.Cognitive failure (dysfiinction or loss of cognitive functions, theprocess by which knowledge is acquired, retained and used) commonlyoccurs in association with central nervous system (CNS) disorders orconditions, including age-associated memory impairment, delirium(sometimes called acute confusional state), dementia (sometimesclassified as. Alzheimer's or non-Alzheimer's type), Alzheimer'sdisease, Parkinson's disease, Huntington's disease (chorea), mentalretardation (e.g. Rubenstein-Taybi Syndrome), cerebrovascular disease(e.g. stroke, ischemia), affective disorders (e.g. depression),psychotic disorders (e.g., schizophrenia, autism (Kanner's Syndrome)),neurotic disorders (i.e. anxiety, obsessive-compulsive disorder),attention deficit disorder (ADD), subdural hematoma, normal-pressurehydrocephalus, brain tumor, head or brain trauma.

Cognitive dysfunction is typically manifested by one or more cognitivedeficits, which include memory impairment (inability to learn newinformation or to recall previously learned information), aphasia(language/speech disturbance), apraxia (impaired ability to carry outmotor activities despite intact motor function), agnosia (failure torecognize or identify objects despite intact sensory function),disturbance in executive functioning (i.e. planning, organizing,sequencing, abstracting).

Cognitive dysfunction causes significant impairment of social and/oroccupational functioning, which can interfere with the ability of anindividual to perform activities of daily living and greatly impact theautonomy and quality of life of the individual. Thus, there is currentlya need for compounds and methods that are useful for improving cognitivefunction in animals.

Phosphodiesterases (E.C. 3.14.17) are a class of enzymes that catalyzethe hydrolysis of the 3′-phosphodiester bond of 3′,5′-cyclicnucleotides. The phosphodiesterase 4 (PDE4) is form specificallyhydrolyzes adenonsine 3′,5′ cyclic monophosphate (cAMP) to form5′-adenosine monophosphate (5′-AMP). cAMP is a well studiedintracellular second messenger that is known to be responsible forregulating a number of cellular processes including transcriptionalregulation. One signaling pathway known to be regulated by intracellularlevels of cAMP is the CREB pathway. The CREB pathway is responsible forregulating transcriptional activity in the brain (including thehippocampus) that leads to protein syntheses required for learning andmemory, especially the consolidation of short-term to long-term memory.It is known that inhibition of PDE4 improves cognitive function inmammals, including contextual memory and object recognition (Tully, et.al., Nature Reviews Drug Discovery, 2003, 2, 267-277; and Barad, et al.,Proc. Natl. Acad. Sci. 1998, 95, 15020-15025). It has also been shown toimprove memory in animals with impaired CREB function (seeBourtchouladze, et. al., Proc Natl Acad Sci USA 2003, 100, 10518-10522).

Numerous companies have invested in the development of specific PDE4inhibitors to treat a variety of diseases, most notably in theanti-inflammatory field (e.g. Rolipram™, and Ariflo™). A commonside-effect of these treatments has been the induction of emesis.Accordingly, there is a particular need for PDE4 inhibiting compoundsthat cause little or no emesis.

SUMMARY OF THE INVENTION

The invention relates to compounds that inhibit PDE4 and that are usefulto improve cognitive function. Accordingly, in one embodiment theinvention provides a compound of formula I:

-   -   wherein:

R₁ is H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkanoyl,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkanoyloxy, (C₃-C₈)cycloalkyl,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, aryl, aryl(C₁-C₆)alkyl,aryl(C₁-C₆)alkoxy, aryl(C₁-C₆)alkanoyl, het, het(C₁-C₆)alkyl,het(C₁-C₆)alkoxy, or het(C₁-C₆)alkanoyl;

n is 1 or 2;

m is 1 or 2;

W is 0, S, or two hydrogens;

X is 0 or N—Y—R₄;

Y is a direct bond, —CH₂—, —C(=0)-, —C(═S)—, -0-, —C(=0)0-, -0C(=0)-,—C(=0)NR_(a)—, —S—, —S(=0)-, —S(=0)₂-, or —S(=0)₂NR_(a)—;

R₄ is H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkanoyl, hydroxy,(C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, halo(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl, carboxy, aryl,aryl(C₁-C₆)alkyl, het, NR_(d)R_(e), —C(=0)NR_(d)R_(e), NR_(d)R_(e)(C₁-C₆)alkyl, or het(C₁-C₆)alkyl;

R_(a) is H, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, (C₁-C₆)alkoxy(C₂-C₆)alkyl,or (C₃-C₈)cycloalkyl(C₁-C₆)alkyl;

Z is a phenyl ring, substituted with one or more substituentsindependently selected from (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,(C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, (C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy, (C₃-C₈)cycloalkyloxy, and(C₃-C₈)cycloalkyl(C₁-C₆)alkoxy; or Z is a phenyl ring that is fused to asaturated, partially unsaturated, or aromatic, mono- or bicyclic ringsystem comprising from about 3 to about 8 atoms selected from carbon,oxygen, and NR_(b), wherein the mono- or bicyclic ring system of Z isoptionally substituted with one or more R_(c) and wherein the phenylring that is fused to the mono- or bicyclic ring system is optionallysubstituted with one or more substituents independently selected from(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C3-C₈)cycloalkyl,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo(C₂-C₆)alkoxy,(C₃-C₈)cycloalkyloxy, and (C₃-C₈)cycloalkyl(C₁-C₆)alkoxy;

R_(b) is absent, H, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,(C₁-C₆)alkoxy(C₂-C₆)alkyl, or (C₃-C₈)cycloalkyl(C₁-C₆)alkyl;

R_(c) is (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkanoyl,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkanoyloxy, (C₃-C₈)cycloalkyl,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, aryl, aryl(C₁-C₆)alkyl,aryl(C₁-C₆)alkoxy, aryl(C₁-C₆)alkanoyl, het, het(C₁-C₆)alkyl,het(C₁-C₆)alkoxy, or het(C₁-C₆)alkanoyl;

-   -   each R_(d) and R_(e) is independently H, hydroxy, (C₁-C₆)alkyl,        (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy,        (C₂-C₆)alkenyloxy, (C₂-C₆)alkynyloxy, (C₁-C₆)alkanoyl,        (C₁-C₆)alkoxycarbonyl, (C₃-C₈)cycloalkyl,        (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, aryl, aryl(C₁-C₆)alkyl,        NR_(f)R_(g), or aryl(C₁-C₆)alkoxy; and    -   each R_(f) and R_(g) is independently H, (C₁-C₆)alkyl,        (C₁-C₆)alkoxy, (C₁-C₆)alkanoyl, (C₁-C₆)alkoxycarbonyl,        (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, aryl,        aryl(C₁-C₆)alkyl, or aryl(C₁-C₆)alkoxy; or R_(f) and R_(g)        together with the nitrogen to which they are attached form a        pyrrolidino, piperidino, piperazine, morpholino, or        thiomorpholino ring;    -   wherein any aryl or het of R₁ or R₄ is optionally substituted        with one or more substitutents independently selected from        (C₁-C₆)alkyl, phenyl, (C₁-C₆)alkoxy, (C₁-C₆)alkanoyl,        (C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkanoyloxy, (C₃-C₈)cycloalkyl,        (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, halo(C₁-C₆)alkyl,        (C₃-C₈)cycloalkyloxy, (C₃-C₈)cycloalkyl(C₁-C₆)alkoxy,        halo(C₂-C₆)alkoxy, cyano, nitro, halo, carboxy or NR_(d)R_(e);    -   and wherein the ring containing X is optionally substituted on        carbon with one or more halo, (C₁-C₆)alkyl, or (C₁-C₆)alkoxy.    -   or a pharmaceutically acceptable salt thereof.

The invention also provides a pharmaceutical composition comprising acompound of formula I, or a pharmaceutically acceptable salt thereof, incombination with a pharmaceutically acceptable diluent or carrier.

The invention also provides a therapeutic method for improving cognitivefunction in an animal comprising administering to the animal aneffective amount of a compound of formula I, or a pharmaceuticallyacceptable salt thereof.

The invention also provides a method for inhibiting PDE4 receptors (invitro or in vivo) comprising contacting the receptors with an effectiveinhibitory amount of a compound of formula I, or a pharmaceuticallyacceptable salt thereof.

The invention also provides a therapeutic method for treating a diseaseor condition in an animal wherein the activity of PDE4 receptors isimplicated and inhibition of PDE4 receptor activity is desiredcomprising administering to the animal an effective PDE4 inhibitingamount of a compound of formula I, or a pharmaceutically acceptable saltthereof.

The invention also provides a method for activating the CREB pathway inan animal comprising administering to the animal an effective CREBpathway activating amount of a compound of formula I, or apharmaceutically acceptable salt thereof.

The invention also provides a method for activating the CREB pathway invitro comprising contacting a sample comprising. SK-N-MC cells stablyexpressing a CRE-luciferase construct with an effective CREB pathwayactivating amount of a compound of formula I, or a pharmaceuticallyacceptable salt thereof.

The invention also provides a therapeutic method for treating apsychiatric disorder in an animal comprising administering to an animalin need thereof an effective amount of a compound of formula I, or apharmaceutically acceptable salt thereof.

The invention provides a compound of formula I, or a pharmaceuticallyacceptable salt thereof for use in medical therapy (e.g. for use inimproving cognitive function or for use in treating a disease orcondition wherein inhibition of PDE4 receptor function is indicated orfor treating a psychiatric disorder), as well as the use of a compoundof formula I for the manufacture of a medicament useful for improvingcognitive function in an animal.

The invention also provides the use of a compound of formula I, or apharmaceutically acceptable salt thereof for the manufacture of amedicament useful for inhibiting PDE4 receptors in an animal.

The invention also provides the use of a compound of formula I, or apharmaceutically acceptable salt thereof for the manufacture of amedicament useful for activating the CREB pathway in an animal.

The invention also provides the use of a compound of formula I, or apharmaceutically acceptable salt thereof for the manufacture of amedicament useful for treating a psychiatric disorder in an animal.

The invention also provides synthetic processes and intermediateddisclosed herein that are useful for preparing compounds of formula (I)or salts thereof. Some compounds of formula I may be useful asintermediates for preparing other compounds of formula I.

Representative compounds of formula I have also been tested and found toproduce little or no emesis.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows data for a representative compound of the invention 50 inthe Contextual Memory Assay (fear conditioning) described hereinbelow.

FIG. 2 shows data for a representative compound of the invention 50 inthe novel object recognition (NOR) assay described hereinbelow.

DETAILED DESCRIPTION

The following definitions are used, unless otherwise described: halo isfluoro, chloro, bromo, or iodo. Alkyl, alkoxy, etc. denote both straightand branched groups; but reference to an individual radical such aspropyl embraces only the straight chain radical, a branched chain isomersuch as isopropyl being specifically referred to. Haloalkoxy denotes astraight chain or branched alkoxy group substituted with one or morehalogen atoms which may be at any carbon atom of the haloalkoxy group.Aryl denotes a phenyl radical or an ortho-fused bicyclic carbocyclicradical having about nine to ten ring atoms in which at least one ringis aromatic; Het encompasses a radical of a monocyclic, bicyclic, ortricyclic ring system containing a total of 3-20 atoms, including one ormore (e.g., 1, 2, 3, 4, 5, or 6) carbon atoms, and one or more (e.g., 1,2, 3, or 4) heteroatoms selected from oxygen, sulfur, and N(X) wherein Xis absent or is H, O, (C₁-C₄)alkyl, phenyl or benzyl, wherein one ormore ring carbons of Het can optionally be substituted with oxo (═O);Heteroaryl encompasses a radical of a monocyclic aromatic ringcontaining five or six ring atoms consisting of carbon and one to fourheteroatoms each selected from the group consisting of non-peroxideoxygen, sulfur, and N(X) wherein X is absent or is H, 0, (C₁-C₄)alkyl,phenyl or benzyl, as well as a radical of an ortho-fused bicyclicheterocycle of about eight to ten ring atoms derived therefrom,particularly a benz-derivative or one derived by fusing a propylene,trimethylene, or tetramethylene diradical thereto. The term Hetencompasses. Heteroaryl. Het and Heteroaryl may be connected to theparent compound via any atom of the Het or Heteroaryl group.Aryl(C₁-C₆)alkyl is an alkyl group substituted with one or more arylgroups; Het(C₁-C₆)alkyl is an alkyl group substituted with one or moreHet groups; and Heteroaryl(C₁-C₆)alkyl is an alkyl group substitutedwith one or more Heteroaryl groups.

The term “animal” as used herein includes birds; reptiles, and mammals(e.g. domesticated mammals and humans).

The term “psychiatric disorder” as used herein includes psychoticdisorders, neurological disorders and neurotic disorders. The termincludes schizophrenia, age-associated memory impairment (AAMI); mildcognitive impairment (MCI), delirium (acute confusional state);depression, dementia (sometimes further classified as Alzheimer's ornon-Alzheimer's type dementia); Alzheimer's disease; Parkinson'sdisease; Huntington's disease (chorea); mental retardation; (e.g.,Rubenstein-Taybi and Downs Syndrome); cerebrovascular disease (e.g.,vascular dementia, post-cardiac surgery); affective disorders; psychoticdisorders; autism (Kanner's Syndrome); neurotic disorders; attentiondeficit disorder (ADD); subdural hematoma; normal-pressurehydrocephalus; brain tumor; head trauma (postconcussional disorder) orbrain trauma.

It will be appreciated by those skilled in the art that compounds of theinvention having a chiral center may exist in and be isolated inoptically active and racemic forms. Some compounds may exhibitpolymorphism. It is to be understood that the present inventionencompasses any racemic, optically-active, polymorphic, orstereoisomeric form, or mixtures thereof, of a compound of theinvention, which possess the useful properties described herein, itbeing well known in the art how to prepare optically active forms (forexample, by resolution of the racemic form by recrystallizationtechniques, by synthesis from optically-active starting materials, bychiral synthesis, or by chromatographic separation using a chiralstationary phase) and how to determine PDE4inhibiting activity using thestandard tests described herein, or using other similar tests which arewell known in the art.

Specific and preferred values listed below for radicals, substituents,and ranges, are for illustration only; they do not exclude other definedvalues or other values within defined ranges for the radicals andsubstituents.

Specifically, (C₁-C₆)alkyl can be methyl, ethyl, propyl, isopropyl,butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl;(C₃-C₈)cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl; (C₃-C₈)cycloalkyl(C₁-C₆)alkyl can be cyclopropylmethyl,cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl,2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, or2-cyclohexylethyl; (C₁-C₆)alkoxy can be methoxy, ethoxy, propoxy,isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, orhexyloxy;. (C₁-C₆)alkanoyl can be acetyl, propanoyl or butanoyl;halo(C₁-C₆)alkyl can be iodomethyl, bromomethyl, chloromethyl,fluoromethyl, trifluoromethyl, 2-chloroethyl, 2-fluoroethyl,2,2,2-trifluoroethyl, or pentafluoroethyl; (C₁-C₆)alkoxycarbonyl can bemethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, pentoxycarbonyl, or hexyloxycarbonyl; (C₂-C₆)alkanoyloxycan be acetoxy, propanoyloxy, butanoyloxy, isobutanoyloxy, pentanoyloxy,or hexanoyloxy; (C₃-C₈)cycloalkyloxy can be cyclopropyloxy,cyclobutyloxy, cyclopropyloxy, cyclohexyloxy, or cyclohexyloxy; aryl canbe phenyl, indenyl, or naphthyl; and heteroaryl can be furyl,imidazolyl, triazolyl, triazinyl, oxazoyl, isoxazoyl, thiazolyl,isothiazoyl, pyrazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl, (orits N-oxide), thienyl, pyrimidinyl (or its N-oxide), indolyl,isoquinolyl (or its N-oxide) or quinolyl (or its N-oxide).

A specific value for R₁ is (C₁-C₆)alkoxy, (C₁-C₆)alkanoyl,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkanoyloxy, (C₃-C₈)cycloalkyl,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, aryl, aryl(C₁-C₆)alkyl,aryl(C₁-C₆)alkoxy, aryl(C₁-C₆)alkanoyl, het, het(C₁-C₆)alkyl,het(C₁-C₆)alkoxy, or het(C₁-C₆)alkanoyl.

A specific value for R₁ is H, (C₁-C₆)alkyl, aryl, aryl(C₁-C₆)alkyl, orhet.

A specific value for R₁ is H, benzyl, indolyl, phenyl, 2-methylpropyl,2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, a-phenylbenzyl,phenethyl, 1-naphthylmethyl, 2-naphthylmethyl, 4-phenylbenzyl,4-ethoxybenzyl, isopropyl, cyclohexylmethyl, 2-methoxyphenyl,3-methoxyphenyl, or 4-methoxyphenyl.

A specific value for n is 1.

A specific value for n is 2.

A specific value form is 1.

A specific value form is 2.

A specific value for X is N—Y—R₄.

A specific value for Y is a direct bond, —CH₂—, —C(-0)-, or —S(=0)₂-.

A specific value for R4 is H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₁-C₆)alkanoyl, hydroxy(C₂-C₆)alkyl, (C₁-C₆)alkoxycarbonyl, carboxy,aryl, aryl(C₁-C₆)alkyl, het, NR_(d)R_(e), —C(═O)NR_(d)R_(e), orhet(C₁-C₆)alkyl.

A specific value for Y—R₄ is H, tert-butoxycarbonyl, formylmethyl,pyridylmethyl, methyl, ethylaminocarbonyl, ethylsulfonyl,benzylsulfonyl, benzyl, acetyl, methoxycarbonylmethyl, methylsulfonyl,ethyl, carboxymethyl, propyl, 2-hydroxyethyl,methoxyaminocarbonylmethyl, benzyloxyaminocarbonylmethyl,prop-2-eneyloxyaminocarbonylmethyl, hydroxyaminocarbonylmethyl,hydroxyacetyl, 2-methylhydrazocarbonylmethyl, hydrazocarbonylmethyl,2,2-dimethylhydrazo-carbonylmethyl, or ethoxycarbonyl.

A specific value for Z is a phenyl ring substituted with one or moresubstituents independently selected from (C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy, (C₃-C₈)cycloalkoxy, and(C₃-C₈)cycloalkyl(C₁-C₆)alkoxy.

A specific value for Z is a phenyl ring that is fused to a saturated,partially unsaturated, or aromatic, mono- or bicyclic ring systemcomprising from about 3 to about 8 atoms selected from carbon, oxygen,and NR_(b), wherein the mono- or bicyclic ring system of Z is optionallysubstituted with one or more 12, and wherein the phenyl ring that isfused is fused to the mono- or bicyclic ring system is optionallysubstituted with one or more substituents independently selected from(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo(C₂-C₆)alkoxy,(C₃-C₈)cycloalkyloxy, and (C₃-C₈)cycloalkyl(C₁-C₆)alkoxy.

A specific group of compounds of formula I are compounds wherein Z hasthe following formula:

wherein

-   -   R₂ is (C₁-C₆)alkyl, or halo(C₁-C₆)alkyl; and    -   R₃ is (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, or        (C₃-C₈)cycloalkyl(C₁-C₆)alkyl.    -   A specific value for R₂ is methyl and R₃ is cyclopropyl.    -   A specific group of compounds of formula I are compounds wherein        Z is selected from a structure of formula III, IV, and V:

that is optionally substituted with one or more substituents selectedfrom (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo(C₂-C₆)alkoxy,(C₃-C₃)cycloalkyloxy, and (C₃-C₈)cycloalkyl(C₁-C₆)alkoxy; wherein p is1, 2, 3, 4, 5, or 6.

A specific group of compounds of formula I are compounds wherein Z isselected from a structure of formula VI, VII, and VIII:

-   -   wherein:        -   R_(j), R_(k), R_(m), R_(n), and R_(p) are each independently            selected from H, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,            (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl,            (C₁-C₆)alkoxy, halo(C₂-C₆)alkoxy, (C₃-C₈)cycloalkyloxy, and            (C₃-C₈)cycloalkyl(C₁-C₆)alkoxy; and p is 1, 2, 3, 4, 5, or            6.

A specific group of compounds of formula I are compounds wherein R_(j),and R_(k) are independently selected from H and methyl; R_(m) ismethoxy; R_(n), is cyclopentyl; R_(p) is ethyl; and p is 3.

A specific group of compounds of formula I are compounds of formula IX:

-   -   wherein R₁, X, W, Z, n and m have any of the values or specific        values defined herein and wherein R_(w), R_(x), R_(y), and R_(z)        are each independently H, halo, or (C₁-C₆) alkyl.

A specific, group of compounds of formula I are compounds of formula X:

-   -   wherein R₁, X, W, Z, n and m have any of the values or specific        values defined herein.

Specific compounds of formula I are presented in the Examples below(e.g. compounds 49-120).

Processes for preparing compounds of formula I are provided as furtherembodiments of the invention and are illustrated by the followingprocedures in which the meanings of the generic radicals are as givenabove unless otherwise qualified.

In one embodiment the invention provides a method for preparing acompound of formula I or a salt thereof as described herein comprising:

-   -   a) deprotecting a corresponding compound that comprises one or        more protecting groups to provide the compound of formula I;    -   b) forming a pharmaceutically acceptable salt from a compound of        formula I; or    -   c) converting a compound of formula I wherein X is N—Y—R₄ and        Y—R₄ taken together is H to a corresponding compound of formula        I wherein Y—R₄ is other than H.

In cases where compounds are sufficiently basic or acidic to form stablenontoxic acid or base salts, administration of the compounds as saltsmay be appropriate. Examples of pharmaceutically acceptable salts areorganic acid addition salts formed with acids which form a physiologicalacceptable anion, for example, tosylate, methanesulfonate, acetate,citrate, malonate, tartarate, succinate, benzoate, ascorbate,α-ketoglutarate, and α-glycerophosphate. Suitable inorganic salts mayalso be formed, including hydrochloride, sulfate, nitrate, bicarbonate,and carbonate salts.

Pharmaceutically acceptable salts may be obtained using standardprocedures well known in the art, for example by reacting a sufficientlybasic compound such as an amine with a suitable acid affording aphysiologically acceptable anion. Alkali metal (for example, sodium,potassium or lithium) or alkaline earth metal (for example calcium)salts of carboxylic acids can also be made.

The compounds of formula I can be formulated as pharmaceuticalcompositions and administered to a mammalian host, such as a humanpatient in a variety of forms adapted to the chosen route ofadministration, i.e., orally or parenterally, by intravenous,intramuscular, topical or subcutaneous routes.

Thus, the present compounds may be systemically administered, e.g.,orally, in combination with a pharmaceutically acceptable vehicle suchas an inert diluent or an assimilable edible carrier. They may beenclosed in hard or soft shell gelatin capsules, may be compressed intotablets, or may be incorporated directly with the food of the patient'sdiet. For oral therapeutic administration, the active compound may becombined with one or more excipients and used in the form of ingestibletablets, buccal tablets, troches, capsules, elixirs, suspensions,syrups, wafers, and the like. Such compositions and preparations shouldcontain at least 0.1% of active compound. The percentage of thecompositions and preparations may, of course, be varied and mayconveniently be between about 2 to about 60% of the weight of a givenunit dosage form. The amount of active compound in such therapeuticallyuseful compositions is such that an effective dosage level will beobtained.

The tablets, troches, pills, capsules, and the like may also contain thefollowing: binders such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, fructose; lactose or aspartame or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring may be added. Whenthe unit dosage form is a capsule, it may contain, in addition tomaterials of the above type, a liquid carrier, such as a vegetable oilor a polyethylene glycol. Various other materials may be present ascoatings or to otherwise modify the physical form of the solid unitdosage form. For instance, tablets, pills, or capsules may be coatedwith gelatin, wax, shellac or sugar and the like. A syrup or elixir maycontain the active compound, sucrose or fructose as a sweetening agent,methyl and propylparabens as preservatives, a dye and flavoring such ascherry or orange flavor. Of course, any material used in preparing anyunit dosage form should be pharmaceutically acceptable and substantiallynon-toxic in the amounts employed. In addition, the active compound maybe incorporated into sustained-release preparations and devices.

The active compound may also be administered intravenously orintraperitoneally by infusion or injection. Solutions of the activecompound or its salts can be prepared in water, optionally mixed with anontoxic surfactant. Dispersions can also be prepared in glycerol,liquid polyethylene glycols, triacetin, and mixtures thereof and inoils. Under ordinary conditions of storage and use, these preparationscontain a preservative to prevent the growth of microorganisms.

The pharmaceutical dosage forms suitable for injection or infusion caninclude sterile aqueous solutions or dispersions or sterile powderscomprising the active ingredient which are adapted for theextemporaneous preparation of sterile injectable or infusible solutionsor dispersions, optionally encapsulated in liposomes. In all cases, theultimate dosage form should be sterile, fluid and stable under theconditions of manufacture and storage. The liquid carrier or vehicle canbe a solvent or liquid dispersion medium comprising, for example, water,ethanol, a polyol (for example, glycerol, propylene glycol, liquidpolyethylene glycols, and the like), vegetable oils, nontoxic glycerylesters, and suitable mixtures thereof. The proper fluidity can bemaintained, for example, by the formation of liposomes, by themaintenance of the required particle size in the case of dispersions orby the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, buffers or sodiumchloride. Prolonged absorption of the injectable compositions can bebrought about by the use in the compositions of agents delayingabsorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are typically prepared by incorporating theactive compound in the required amount in the appropriate solvent withvarious of the other ingredients enumerated above, as required, followedby filter sterilization. In the case of sterile powders for thepreparation of sterile injectable solutions, the preferred methods ofpreparation are vacuum drying and the freeze drying techniques, whichyield a powder of the active ingredient plus any additional desiredingredient present in the previously sterile-filtered solutions.

For topical administration, the present compounds may be applied in pureform, i.e., when they are liquids. However, it will generally bedesirable to administer them to the skin as compositions orformulations, in combination with a dermatologically acceptable carrier,which may be a solid or a liquid.

Useful solid carriers include finely divided solids such as talc, clay,microcrystalline cellulose, silica, alumina and the like. Useful liquidcarriers include water, alcohols or glycols or water-alcoho/glycolblends, in which the present compounds can be dissolved or dispersed ateffective levels, optionally with the aid of non-toxic surfactants.Adjuvants such as fragrances and additional antimicrobial agents can beadded to optimize the properties for a given use. The resultant liquidcompositions can be applied from absorbent pads, used to impregnatebandages and other dressings, or sprayed onto the affected area usingpump-type or aerosol sprayers.

Thickeners such as synthetic polymers, fatty acids, fatty acid salts andesters, fatty alcohols, modified celluloses or modified mineralmaterials can also be employed with liquid carriers to form spreadablepastes, gels, ointments, soaps, and the like, for application directlyto the skin of the user.

Useful dosages of the compounds of formula I can be determined bycomparing their in vitro activity, and in vivo activity in animalmodels. Methods for the extrapolation of effective dosages in mice, andother animals, to humans are known to the art.

The amount of the compound, or an active salt or derivative thereof,required for use in treatment will vary not only with the particularsalt selected but also with the route of administration, the nature ofthe condition being treated and the age and condition of the patient andwill be ultimately at the discretion of the attendant physician orclinician.

In general, however, a suitable dose will be in the range of from about0.1 to about 100 mg/kg, e.g., from about 10 to about 75 mg/kg of bodyweight per day, such as 3 to about 50 mg per kilogram body weight of therecipient per day, preferably in the range of 0.5 to 90 mg/kg/day, mostpreferably in the range of 1 to 60 mg/kg/day. The compound isconveniently administered in unit dosage form; for example, containing 1to 1000 mg, conveniently 10 to 750 mg, most conveniently, 50 to 500 mgof active ingredient per unit dosage form. Ideally, the activeingredient should be administered to achieve peak plasma concentrationsof the active compound of from about 0.5 to about 75 μM, preferably,about 1 to 50 μM, most preferably, about 2 to about 30 μM. This may beachieved, for example, by the intravenous injection of a 0.05 to 5%solution of the active ingredient, optionally in saline, or orallyadministered as a bolus containing about 1-100 mg of the activeingredient. Desirable blood levels may be maintained by continuousinfusion to provide about 0.01-5.0 mg/kg/hr or by intermittent infusionscontaining about 0.4-15 mg/kg of the active ingredient(s). The desireddose may conveniently be presented in a single dose or as divided dosesadministered at appropriate intervals, for example, as two, three, fouror more sub-doses per day. The sub-dose itself may be further divided,e.g., into a number of discrete loosely spaced administrations.

The compounds of the invention can also optionally be administered incombination with one or more other therapeutic agents that are effectiveto improve cognition or treat a psychiatric disorder and/or one or moretherapeutic agents that are effective to treat age-associated memoryimpairment (AAMI); mild cognitive impairment (MCI), delirium (acuteconfusional state); dementia (sometimes further classified asAlzheimer's or non-Alzheimer's type dementia); Alzheimer's disease;Parkinson's disease; Pick's Disease, multiple sclerosis, Huntington'sdisease (chorea); mental retardation; (e.g., Rubenstein-Taybi, FragileX, Angelman Syndrome, Coffin-Lowry Syndrome and Downs Syndrome);Wilson's Disease, Creutzfeldt-Jacob Disease, Neurofibromatosis type 1,Wernicke-Korsakoff Syndrome, cerebrovascular disease (e.g., vasculardementia, post-cardiac surgery); affective disorders; psychoticdisorders; autism (Kanner's Syndrome); neurotic disorders; attentiondeficit disorder (ADD); subdural hematoma; normal-pressurehydrocephalus; brain tumor, head trauma. (postconcussional disorder) andbrain trauma (see DSM-IV, APA 1994).

The ability of a compound to inhibit PDE 4 activity can be determinedusing assays that are known, or it can be determined using the followingassay.

PDE4 Inhibition Assay

PDE4 from human U-937 cells was used (see T. J. Torphy, et al., J.Pharmacol. Exp. Ther., 1992, 263,1195-1205). Test compound at variousconcentration and/or vehicle was preincubated with 2 pg/ml enzyme inTris-HCl buffer pH 7.5 for 15 minutes at 25° C. The reaction wasinitiated by addition of 1 μM cAMP and 0.01 μM [³H]-cAMP for another 20minute incubation period and terminated at 100° C. The resulting[³H]-AMP was converted to [³H]-adenosine by addition of snake venomnucleotidase and separated by AG I-X2 resin. An aliquot was removed andcounted to determine the amount of [³H]-adenosine formed. Results wereconverted to percent inhibition and IC₅₀ determined using XLfit fromIDBS (ID Business Solutions Ltd., 2 Occam Court, Surrey Research Park,Guildford, Surrey, GU2 7QB UK).

Representative compounds of the invention were tested and found to havesignificant PDE4 inhibition in this assay.

The ability of a compound to activate CREB can be determined using thefollowing assay.

CREB Activiation Assay

The following CRE-Luci assay is a high throughput, well-based method foridentifying compounds that enhance cognition by increasing CREB pathwayfunction. The assay enables the identification of cognitive enhancersthat do not affect CREB pathway function alone, but act to increase(enhance) CREB pathway function in combination with a CREB functionstimulating agent.

The assay is carried out by (a) contacting host cells (particularlycells of neural origin (e.g. human neuroblastoma SK-N-MC cells) having aluciferase gene operably linked to a CRE promoter with a test compoundand a suboptimal dose of a CREB function stimulating agent (e.g.,forskolin); (b) determining luciferase activity in the host cells whichhave been contacted with the test compound and with the CREB functionstimulating agent; and (c) comparing the luciferase activity determinedin step (b) with the luciferase activity in control cells which havebeen contacted with the CREB function stimulating agent and which havenot been contacted with the test compound (i.e., control cells whichhave been contacted with the CREB function stimulating agent alone).

Host cells comprising luciferase gene operably linked to a CRE-promotercan be manufactured by introducing into cells a DNA construct comprisinga luciferase gene operably linked to a CRE promoter. DNA constructs canbe introduced into cells according to methods known in the art (e.g.,transformation, direct uptake, calcium phosphate precipitation,electroporation, projectile bombardment, using liposomes). Such methodsare described in more detail, for example, in Sambrooke et al.,Molecular cloning: A laboratory Manual, 2^(nd) edition (New York: ColdSpring Harbor University Press) (1989); and Ausubel, et al., CurrentProtocols in Molecular Biology (New York: John Wiley & Sons) (1998).

SK-N-MC cells stably transfected with CRE-luc construct are seeded in96-well, white assay plates (PerkinElmer) at a concentration of 20,000cells/well in 100 μL MEM complete media. These cells are incubated in aCO₂ incubator under standard cell culture condition. After 18 to 24hours of incubation, cells are treated with either a vehicle control(DMSO, Sigma), the test compounds (5 μM final concentration), or apositive control (HT-0712, 5 μM final concentration) (16 wells for eachtreatment) for 2 hours. Forskolin (5 μM final concentration, Sigma) isthen added to 8 wells of each treatment group and an equivalent amountof DMSO is added to the other 8 wells. Six hours after forskolinaddition, luciferase activity is measured by adding 25 μL of assayreagent (BriteLite kit, PerkinElmer) to each well. After incubation atroom temperature for 3 minutes, luminescence is detected using a WallacVictor5 plate reader (PerkinElmer). The transcription induction ratio isderived by normalizing the luciferase activity of the compound orpositive control in the presence of forskolin over forskolin treatmentalone. The compound treatment alone serves as control to determinewhether compound can active CRE promoter by itself.

Representative compounds of the invention were found to increase CREBpathway function using this assay.

The ability of a compound to modulate cognitive behavior can beevaluated using the following Contextual Memory Assay.

Contextual Memory Assay: Fear Conditioning

Contextual memory is a form of Pavlovian fear conditioning in which anaive mouse is placed into a novel chamber (context) containing distinctvisual, olfactory and tactile cues. After several minutes ofacclimation, the mouse receives a brief, mild electric shock to itsfeet. From this negative experience, the mouse will remember for monthsthat that chamber is dangerous. When placed back into the same contextat some later time after training, the mouse's natural response todanger is to “freeze,” sitting stone still for many seconds. This issimilar to what happens to humans when they experience fear. The percentof time during an observation period that the mouse spends frozenrepresents a quantitative measure (memory score) of its memory of thecontext.

Contextual conditioning has been extensively used to investigate theneural substrates mediating fear-motivated learning (Phillips, LeDoux,Behav Neurosci, 1992, 106, 274-285; Kim, et. al., Behav Neurosci, 1993,107, 1093-1098; Bourtchouladze, et al., Learn Mem, 1998, 5, 365-374; andBourtchouladze et al., Cell, 1994, 79, 59-68). Contextual conditioninghas been also used to study the impact of various mutations onhippocampusdependent memory (Bourtchouladze, et al., Learn Mem, 1998, 5,365-374; Bourtchouladze, et. al., Cell, 1994, 79, 59-68.; Silva, et.al., Curr Biol, 1996, 6, 1509-1518; Kogan, et al., Curr Biol, 1997, 7,1-11; Abel, et. al., Cell, 1997, 88, 615-626; and Giese, et aL, Science,1998, 279, 870-873); and strain and genetic background differences inmice (Logue, et al., Behav Neurosci, 1997, 111, 104-113; and Nguyen, et.al., Learn Mem, 2000, 7, 170-179). Because robust memory can betriggered with a few minutes training session, contextual conditioninghas been especially useful to study biology of temporally distinctprocesses of short- and longterm memory (Kim, et. al., Behav Neurosci,1993, 107, 1093-1098; Bourtchouladze, et. al., Learn Mem. 1998, 5,365-374; Bourtchouladze, et. aL, Cell, 1994, 79, 59-68; and Abel, et.al., Cell, 1997, 88, 615-626). As such, contextual conditioning is anexcellent model to evaluate the role of various novel drug-compounds inhippocampus-dependent memory.

Young-adult (10-12 weeks old) C57BL/6 male mice and. Sprague Dawley malerats of 250-300 g (Taconic, NY) were used. Mice were group-housed (5mice) in standard laboratory cages while rats were housed in pairs andmaintained on a 12:12 light-dark cycle. The experiments were alwaysconducted during the light phase of the cycle. With the exception oftesting times, the mice had ad lib access to food and water. Theexperiments were conducted according with the Animal Welfare assurance#A3280-01 and animals were maintained in accordance with the animalWelfare Act and Department of Health and Human Services guide.

To assess contextual memory, a modified contextual fear conditioningtask originally developed for evaluation of memory in CREB knock-outmice was used (Bourtchouladze, et. al., Cell, 1994, 79, 59-68). On thetraining day, the mouse was placed into the conditioning chamber (MedAssociates, Inc., VA) for 2 minutes before the onset of unconditionedstimulus (US), 0.5 mA, of 2 sec foot shock. The US was repeated twotimes with a 1 min inter-trial interval between shocks. Training wasperformed by automated software package (Med Associates, Inc., VA).After the last training trial, the mice were left in the conditioningchamber for another 30 sec and were then placed back in their homecages. 24 hours after training, the mouse was placed into the sametraining chamber and contextual memory was assessed by scoring freezingbehavior (‘freezing’ serves as memory score). Freezing was defined asthe complete lack of movement in intervals of 5 seconds (Kim, et. al.,Behav Neurosci, 1993, 107, 1093-1098; Phillips, LeDoux, Behav Neurosci,1992, 106, 274-285; Bourtchouladze, et. al., Learn Mem, 1998, 5,365-374; and Bourtchouladze, et. al., Cell, 1994, 79, 59-68; Abel, etal., Cell, 1997, 88, 615-626). Total testing time lasted 3 minutes.After each experimental subject, the experimental apparatus wasthoroughly cleaned with 75% ethanol, water, dried, and ventilated for afew minutes.

All experiments were designed and performed in a balanced fashion,meaning that (i) for each experimental condition (e.g. a specificdose-effect) an equal number of experimental and control mice was used;(ii) each experimental condition was replicated 2-3 independent times,and replicate days were added to generate final number of subjects. Theproceeding of each experiment was filmed. In each experiment, theexperimenter was unaware (blind) to the treatment of the subjects duringtraining and testing. Data were analyzed by Student's unpaired t testusing a software package (Statview 5.0.1; SAS Institute, Inc). Allvalues in the text and figures are expressed as mean±SEM.

Compounds were dissolved in 1% DMSO/PBS and, administeredintraperitonially (I.P.) in a volume of 8 mL/kg 20 min before training.Control animals received vehicle alone (1% DMSO/PBS). For oraladministration the compounds were dissolved in 30% DMSO/1.4% CMC.Consequently, control animals received 30% DMSO/1.4% CMC. For eachtraining and drug-injecting procedure, an experimentally naive group ofanimals were used.

To evaluate the effects of Compound 50 on contextual memory, mice wereinjected with Compound 50 or vehicle 20 minutes before training andtrained with 2 training trials (US). Mice were than tested in the samecontext 24 hours after training (FIG. 1). 1 mg/kg Compound 50-injectedmice froze significantly more than vehicle injected mice (32.5+3.2% vs.22.3+3.2%; n=22 and n=20 for Compound 50 and controls, respectively;p<0.05, Student's unpaired t test). Similarly, 10 mg Compound50-injected mice showed significantly more memory than vehicle injectedmice (38.3% vs. 22.3+3.2%; n=22 and n=20, for Compound 50 and controls,respectively; p<0.005, Student's unpaired t test), while 0.1 mg/kgCompound 50 had no significant effect on contextual memory.

The ability of a compound to modulate cognitive behavior can also beevaluated using the following Object Recognition Assay.

Object Recognition Assay

Object recognition is an ethologically relevant task for rodents, whichdoes not result from negative reinforcement (foot shock). This taskrelies on the natural curiosity of rodents to explore novel objects intheir environments more than familiar ones. Obviously, for an object tobe “familiar,” the animal must have attended to it before and rememberedthat experience. Hence, animals with better memory will attend andexplore a new object more than an object familiar to them. Duringtesting, the animal is presented with the training object and a second,novel one. Memory of the training object renders it familiar to theanimal, and it then spends more time exploring the new novel objectrather than the familiar one (Bourtchouladze, et. al., Proc Natl AcadSci USA, 2003, 100, 10518-10522). Recent neuroimaging studies in humansdemonstrated that memory in object recognition depends on prefrontalcortex (PFC) (Deibert, et. al., Neurology, 1999, 52, 1413-1417).Consistent with these findings, rats with the PFC lesions show poorworking memory when they are required to discriminate between familiarand novel objects (Mitchell, Laiacona, Behav Brain Res, 1998, 97,107-113). Other studies on monkeys and rodents suggest that thehippocampus is important for novel object recognition (Teng, et. al., J.Neurosci, 2000, 20, 3853-3863; Mumby, Brain Res, 2001, 127, 159-181).Hence, object recognition provides an excellent behavioral model toevaluate drug-compound effects on cognitive task associated withfunction of hippocampus and cortex.

Prior to initiation of training, animals were handled for 3-5 minutesfor 5 days. Training and testing were performed identically for mice andrats with an exception of training apparatus dimensions (for mice: aPlexiglas box of L=48 cm; W=38 cm and H=20 cm; for rats: a Plexiglas boxof L=70 cm; W=60 cm and H=35 cm). The day before training, an individualanimal was placed into a training apparatus located in a dimly lit roomand allowed to habituate to the environment for 15 minutes (also seePittenger, et. al., Neuron, 2002, 34, 447-462; and Bourtchouladze, et.al., Proc Natl Acad Sci USA, 2003, 100, 10518-10522). Training wasinitiated 24 h hours after habituation. An animal was placed back intothe training box, which contained two identical objects (e.g. a smallconus-shape object), and was allowed to explore these objects. Theobjects were placed into the central area of the box and the spatialposition of objects (left-right sides) was counterbalanced betweensubjects. Animals were trained for 15 minutes. To test for memoryretention, animals were observed for 10 minutes 24 hours after training.A rodent was presented with two objects, one of which was used duringtraining, and thus was ‘familiar’ and the other of which was novel (e.g.a small pyramid-shape object). To insure that the discrimination targetsdo not differ in smell, after each experimental subject, the apparatusand the objects were thoroughly cleaned with 90% ethanol, dried andventilated for a few minutes.

The experiments were videotaped via an overhead video camera system.Types were then reviewed by a blinded observer and the followingbehavioral parameters were determined: time of exploration of an eachobject; the total time of exploration of the objects; number ofapproaches to the objects; and time (latency) to first approach to anobject. The discrimination index—memory score—was determined asdescribed previously (Ennaceur, Aggleton, Behav Brain Res, 1997, 88,181-193; and Bourtchouladze, et. at, Proc Natl Acad Sci USA, 2003, 100,10518-10522). This Data was analyzed by Student's unpaired t test usinga, software package (Statview 5.0.1; SAS Institute, Inc). All values inthe text and figures are expressed as mean±SEM.

The invention will now be illustrated by the following non-limitingexamples.

LC/MS Protocol

Equipment: Waters 2695 Separations Unit, 2487 Dual Absorbance Detector,Micromass ZQ fitted with ESI Probe.

Sample Preparation: Materials dissolved in acetonitrile and diluted withequal volume water.

LC Protocol: Observed, 254 nm. Solvent system, acetonitrile (0.1% formicacid) and water (0.1% formic acid). Column, XTerra MS. C-18 3.5 uM(2.1×50 mm), 30 C oven temperature. Run time, 10 min. Flow rate 0.3ml/min.

Inlet Method:

Time % acetonitrile % water (0.1% (min) (0.1% formic acid) formic acid)0 10 90 5 90 10 7 90 10 7.5 10 90NMR Protocol

Analysis was carried out on a VarianMercury 300 MHz NMR. Samples wereanalyzed in either chloroform-D or dimethyl sulfoxide-D₈. Forchloroform-D samples, tetramethylsilane (TMS) was used as an internalstandard with the TMS resonance set to a chemical shift of 0.00 ppm for¹H NMR spectra. The ¹³C NMR spectra were set to the internal residualchloroform resonance at 77.23 ppm. For dimethyl sulfoxide-D₈, theresidual central resonance peak at 2.54 ppm for ¹H and 39.51 for ¹³C wasused as reference for chemical shift assignment. DEPT experiments areexpressed in the ¹³C NMR listings by notation of their respectivemultiplicity: CH, CH₂, and CH3.

PREPARATIVE EXAMPLES 1-20

Intermediate nitrogen containing heterocyclic diones were prepared asillustrated below.

Preparative Example 11-Benzyl-3(S)-(2′-methylbenzyl)-piperazine-2,5-dione

A solution of Boc-2-m ethyl-L-phenylalanine (2.79 g, 10 mmol) in DMF (25mL) was treated sequentially with HOBt (2.03 g, 15 mmol), DIEA (4.35 mL,25 mmol), N-benzylglycine ethyl ester (2.03 mL, 11 mmol), and HBTU (5.69g, 15 mmol). The resulting solution was allowed to stir for 16 hr afterwhich time the mixture was poured onto a mixture of 1 N HCl. (50 mL) andEtOAc (50 mL). The organic portion was separated and further extractedwith a saturated NaHCO₃ solution (50 mL) follow by brine (50 mL). Theorganicphase was dried over MgSO₄, filtered and evaporated to an oil,which was purified by silica gel flash chromatography with 20% then 30%EtOAc/hexanes as eluant to afford product as a solid (4:31 g, 95%).LC/MS 7.43 min, [M+1]⁺ 455.

The coupled prochict was dissolved in 4N solution of hydrogen chloridein1,4-dioxane and stirred for 3 hr at room temperature then evaporated todryness and placed on a vacuum pump for 24 hr. The crude deprotectedmaterial was then dissolved in MeOH (10 mL) and treated with a saturatedaqueous solution of NaHCO₃ (˜10 mL). The solution rapidly solidified andthe resulting paste filtered with the aid of water and air dried toprovide solid product (2.83 g, 97%). ¹H NMR (DMSO-_(d6)) 2.28 (s, 3 H),2.53-2.55 (m, 1 H), 2.83 (d, J=17.1, 1 H), 3.05 (dd, J=14.1, 5.1, 1 H),3.05 (dd, J=13.8, 5.1, 1 H), 3.46 (d, J=17.1, 1 H), 4.21-4.25 (m, 1 H),4.39 (d, J=14.5, 1 H), 4.49 (d, J=14.5, 1 H) 6.88-6.93 (m, 1 H), 7.01(d,3=7.3, 1 H), 7.11-7.14 (m, 2 H), 7.19-7.22 (m, 2 H), 7.33-7.41 (m, 3 H),8.35 (br d, J=2.6, 1 H). ¹³C NMR 19.3 (CH₃), 36.2 (CH₂), 48.3 (CH₂),48.5 (CH), 55.7 (CH), 125.5 (CH), 126.8 (CH), 127.5 (CH), 128.2 (CH),128.5 (CH), 130.2 (CH), 130.5 (CH), 134.1, 135.8, 136.9, 164.9, 166.0.LC/MS 3.78 min, [M+1]⁺ 309.

Preparative Example 2 1-Benzyl-3(R)-(benzyl)-piperazine-2,5-dione

Colorless solid (88%); ¹H NMR (DMSO-_(d6)) 2.69 (d, J=17.1, 1 H), 2.93(dd, J=13.6, 4.8, 1 H), 3.20 (dd, J=13.6, 4.2, 1 H), 3.49 (d, J=17.1, 1H), 4.22 (d, J=14.5, 1 H), 4.31 (m, 1 H), 4.63 (d, J=14.5, 1 H),7.11-7.25 (m, 7 H), 7.32-7.38 (m, 3 H), 8.379 (s, 1 H). LC/MS 4.98 min,[M+1]⁺ 295.

Preparative Example 31-Benzyl-3(S)-(3′-methylbenzyl)-piperazine-2,5-dione

Colorless solid (100%); ¹H NMR (DMSO-_(d6)) 2.23 (s, 1 H), 2.53-2.55 (m,1 H), 2.78 (d, J=17.1, 1 H), 2.91 (dd, J=13.4, 4.8, 1 H), 3.15 (dd,J=13.4, 4.0, 1 H), 3.50 (d, J=17.4, 1 H), 4.24-4.29 (m, 2 H), 4.59 (d,J=14.5, 1 H) 6.89-6.92 (m, 1 H), 7.01 (br s, 1 H), 7.05-7.06 (m, 2 H),7.12-7.16 (m, 2 H), 7.30-7.37 (m, 3 H), 8.35 (br s, 1 H). ¹³C NMR 20.9,48.3, 55.5, 127.0, 127.3, 127.4, 127.9, 128.0, 128.5, 130.7, 135.5,135.7, 137.0, 164.9, 165.4. LC/MS 4.53 min, [M+1]⁺ 309.

Preparative Example 41-Benzyl-3(S)-(4′-methylbenzyl)-piperazine-2,5-dione

Colorless solid (94%); ¹H NMR (DMSO-_(d6)) 2.25 (s, 3 H), 2.53-2.55 (m,1 H),2.69 (d, J=17.4, 1 H), 2.89 (dd, J=13.4, 4.6, 1 H), 3.15 (dd,J=13.4, 4.0, 1 H), 3.49 (d, J=17.1, 1 H), 4.20 (d, J=14.3, 1 H), 4.28(br t, J=4.0, 1 H), 4.64 (d, J=14.5, 1 H), 6.97 (m, 4 H), 7.14-7.17 (m,2 H), 7.33-7.36 (m, 3 H), 8.35 (br s, 1 H). ¹³C NMR 20.6, 38.8, 48.2,48.3, 55.6, 127.4, 128.3, 128.4, 128.6, 129.9, 132.3, 135.7, 135.7,164.9, 165.4. LC/MS 4.01 min, [M+1]⁺ 309.

Preparative Example 51-Benzyl-3(S)-(2′-methoxylbenzyl)-piperazine-2,5-dione

Colorless solid (78%); ¹H NMR (DMSO-_(d6)) 2.99 (dd, J=13.4, 5.9, 1 H),3.14 (obs dd, J=13.4, 5.3, 1 H), 3.19 (obs d, J=17.1, 1 H), 3.51 (d,J=17.1, 1 H), 3.78 (s, 3 H), 4.15-4.20 (m, 1 H), 4.47 (s, 2 H) 6.75 (t,J=7.5, 1 H), 6.97 (d, J=8.1, 1 H), 7.03 (dd, J=7.3, 1.5, 1H), 7.22-7.28(m, 3 H), 7.33-7.42 (m, 3 H), 8.12 (d, J=2.2, 1 H). LC/MS 5.02 min,[M+1]⁺ 325.

Preparative Example 61-Benzyl-3(S)-(3′-methoxylbenzyl)-piperazine-2,5-dione

Colorless solid (60%); ¹H NMR (DMSO-_(d6)) 2.86 (d, J=17.6, 1 H), 2.92(obs dd, J=13.4, 4.6, 1 H), 3.17 (dd, J=13.4, 4.2, 1 H), 3.52 (d,J=17.4, 1 H), 3.72 (s, 3 H), 4.27 (d, J=14.7, 1 H), 4.32 (m, 1 H), 4.60(d, J=14.5, 1 H), 6.69 (d, J=7.5, 1 H), 6.75 (m, 1 H), 6.83 (dd, J=8.1,2.4, 1 H), 7.07 (d, J=7.9, 1 H), 7.11-7.14 (m, 3 H), 7.30-7.36 (m, 3 H),8.39 (s, 1 H). LC/MS 4.95 min, [M+1]⁺ 325.

Preparative Example 71-Benzyl-3(S)-(4′-methoxylbenzyl)-piperazine-2,5-dione

Colorless solid (83%); ¹HNMR (DMSO-_(d6)) 2.64 (d, J=17.4, 1 H), 2.84(dd, J=13.6, 4.6, 1 H), 3.13 (dd, J=13.6, 3.7, 1 H), 3.49 (d, J=17.4, 1H), 3.71 (s, 3 H), 4.15 (d,J 14.5, 1 H), 4.25 (m, 1 H), 4.69 (d, J=14.5,1 H), 6.67 (d, J=8.8, 2 H), 6.97 (d, J=8.8, 2 H), 7.16-7.19 (m, 2 H),7.35-7.37 (m, 3 H), 8.34 (d, J=2.3, 1 H). LC/MS 4.93 min, [M+1]⁺ 325.

Preparative Example 81-Benzyl-3(S)-(4′-ethoxylbenzyl)-piperazine-2,5-dione

Colorless solid (90%); ¹H NMR (DMSO-_(d6)) 1.33 (t, J=7.0, 1 H), 2.64(d, J=17.4, 1 H), 2.84 (dd, J=13.6, 4.8, 1 H), 3.12 (dd, J=13.6, 3.7, 1H), 3.48 (d, J=17.1, 1 H), 3.91-3.99 (m, 2 H), 4.17 (d, J=14.5, 1 H),4.24 (br s, 1 H), 4.67 (d, J=14.5, 1 H), 6.66 (d, J=8.6, 2 H), 6.96 (d,J=8.8, 2 H), 7.16-7.19 (m, 2 H), 7.34-7.37 (m, 3 H), 8.35 (br s, 1 H).LC/MS 4.33 min, [M+1]⁺ 339.

Preparative Example 9 1-Benzyl-3(S)-(2-phenethyl)-piperazine-2,5-dione

Colorless solid (92%); ¹HNMR (DMSO-_(d6)) 2.02-2.11 (m, 2 H), 2.64-2.71(m, 2 H), 3.83 (d, J=17.1, 1 H), 3.95 (d, J=17.4, 1 H), 4.00-4.01 (m, 1H), 4.52 (d, J=14.7, 1 H), 4.63 (d, J=14.7, 1 H), 7.19-7.42 (m, 10 H),8.55 (br d, J=1.8, 1 H). ¹³C NMR 30.3, 35.0, 48.5, 49.1, 54.0, 125.9,127.5, 127.8, 128.4, 128.6, 136.4, 141.2, 165.5, 166.3. LC/MS 4.72 min,[M+1]⁺ 309.

Preparative Example 10 1-Benzyl-3(R)-(2-phenethyl)-piperazine-2,5-dione

Colorless solid (92%). LC/MS 5.32 min, [M+1]⁺ 309.

Preparative Example 111-Benzyl-3(S)-(3-phenylpropyl)-piperazine-2,5-dione

Colorless solid (91%); ¹H NMR (DMSO-_(d6)) 1.60-1.68 (m, 2 H), 1.75-1.84(m, 2 H), 2.61 (t, J=7.6), 3.77 (d, J=17.3, 1 H), 3.87 (d, J=17.3, 1 H),4.47 (d, J=14.9, 1 H), 4.62 (d, J=14.6, 1 H), 7.20-7.23 (m, 3 H),7.27-7.41 (m, 7 H), 8.42 (d, J=2.3, 1 H). LC/MS 5.59 min, [M+1]⁺ 323.

Preparative Example 121-Benzyl-3(S)-(1′-naphthylmethyl)-piperazine-2,5-dione

Colorless solid (89%); ¹H NMR (DMSO-_(d6)) 2.96 (d, J=17.1, 1 H), 3.41(d, J 17.1, 1 H), 3.50-3.64 (m, 2 H), 4.35 (m, 3 H), 7.06-7.09 (m, 2 H),7.29-7.38 (m, 5 H), 7.53-7.63 (m, 2 H), 7.84-7.87 (m, 1 H), 7.97 (dd,J=7.3, 2.4, 1 H), 8.18 (d, J=7.5, 1 H), 8.37 (d, J=2.9, 1 H)). ¹³C NMR36.0, 48.3, 48.4, 55.8, 124.0, 125.2, 125.6, 126.1, 127.4, 127.9, 128.5,131.9, 132.2, 133.4, 135.8, 164.9, 165.9. LC/MS 4.72 min, [M−Fl]⁺ 345.

Preparative Example 131-Benzyl-3(S)-(2′-naphthylmethyl)-piperazine-2,5-dione

Colorless solid (92%); ¹H NMR (DMSO-_(d6)) 2.81 (d, J=17.1, 1 H), 3.14(dd, J=13.6, 4.8, 1 H), 3.39 (dd, J=13.4, 4.4, 1 H), 3.52 (d, J=17.4, 1H), 4.19 (d, J=14.7, 1 H), 4.68 (d, J=14.5, H), 7.01-7.03 (m, 2 H),7.13-7.17 (m, 2 H), 7.23 (d, J=7.3, 1 H), 7.31 (dd, J=8.6, 1.5, 1H),7.51-7.56 (m, 2 H), 7.70 (s, 1 H), 7.74 (d, J=8.4, 1 H), 7.82-7.84 (m, 1H), 7.88-7.91 (m, 1 H), 8.50 (s, 1 H)). ¹³C NMR 39.2, 48.3, 48.3, 55.6,125.7, 126.0, 127.3, 127.5, 127.5, 127.5, 127.9, 128.2, 128.3, 128.7,131.9, 132.8, 133.5, 135.6, 164.7, 165.3. LC/MS 4.72 min, [M+1]⁺ 345.

Preparative Example 141-Benzyl-3(S)-(4′-biphenylmethyl)-piperazine-2,5-dione

Colorless solid (99%); ¹H NMR (DMSO-_(d6)) 2.78 (d, J=17.4, 1 H), 2.97(dd, J=13.4, 4.8, 1 H), 3.23 (dd, J=13.2, 3.9, 1 H), 3.55 (d, =17.4, 1H), 4.18 (d, J=14.5, 1 H), 4.73 (d, J=14.2, H), 7.17-7.20 (m, 4 H),7.32-7.35 (m, 2 H), 7.39-7.53 (m, 4 H), 7.62-7.65 (m, 2 H), 8.42 (s, 1H). ¹³C NMR 38.7, 40.3 (methylene resonance obscured by solvent, visiblein DEPT experiment), 48.3, 48.4, 55.5, 126.2, 126.4, 127.3, 127.5,128.4, 128.4, 130.6, 134.8, 135.7, 138.4, 139.6, 164.9, 165.4. LC/MS5.39 min, [M+1]⁺ 371.

Preparative Example 151-Benzyl-3(S)-(diphenylmethyl)-piperazine-2,5-dione

Colorless solid (99%); ¹H NMR (DMSO-_(d6)) 3.02 (d, J=17.1, 1 H), 3.51(dd, J=17.4, 4.8, 1 H), 4.20 (d, J=14.5, 1 H), 4.60 (s, 1 H), 4.61 (d,J=4.6, 1 H), 4.80-4.83 (m, 1 H), 7.12-7.16 (m, 3 H), 7.22-7.38 (m, 12H). ¹³C NMR 49.3, 49.4, 55.4, 59.0, 127.3, 127.5, 128.2, 128.9, 128.9,129.2, 129.3, 130.1, 136.6, 140.4, 141.1, 166.0, 166.6. LC/MS 5.28 min,[M+1]⁺ 371.

Preparative Example 161-Benzyl-3(S)-(cyclohexylmethyl)-piperazine-2,5-dione

Colorless solid (93%); ¹HNMR (DMSO-_(d6)) 0.84-0.99 (m, 2 H), 1.12-1.24(m, 3 H), 1.46-1.80 (m, 8 H), 3.75 (d, J=17.1, 1 H), 3.93 (obs m, 1 H),3.94 (d, J=17.1, 1 H), 4.49 (d, J=14.7, 1 H), 4.60 (d, J=14.7, 1 H),7.27-7.42 (m, 5 H), 8.46 (s, 1 H). ¹³C NMR 25.6, 25.8, 26.0, 31.9, 32.8,33.2, 40.9, 48.4, 49.0, 52.5, 127.4, 127.8, 128.6, 136.4, 165.4, 167.0.LC/MS 4.84 min, [M+1]⁺ 301.

Preparative Example 17Tetrahydro-1,3-bis(phenylmethyl)-(3S)-1H-1,4-Diazepine-2,5-dione, CAS[612844-06-1]

Colorless solid (64%); ¹HNMR (DMSO-_(d6)) 2.15-2.27 (m, 1 H), 2.43-2.51(m, 1 H), 2.84 (dd, J=14.3, 7.7, 1 H), 3.11-3.21 (m, 2 H), 4.00-4.10 (m,1 H), 4.50 (d, J=14.9, 1 H), 4.58 (d, J=14.7, 1 H), 4.77-4.82 (m, 1 H),7.16-7.53 (m, 10 H). ¹³C NMR 34.8, 35.3, 42.1, 49.4, 52.8, 126.2, 127.2,127.7, 128.1, 128.5, 129.4, 137.9, 138.2, 170.7, 170.9. LC/MS 5.30 min,[M+1]⁺ 309.

Preparative Example 18Tetrahydro-1,3-bis(phenylmethyl)-(3R)-1H-1,4-Diazepine-2,5-dione

Colorless solid (57%). LC/MS 5.30 min, [M+1]⁺ 309.

Preparative Example 19 Tetrahydro-1,5-bis(phenylmethyl)-(5S)-1H-1,4-Diazepine-3,7-dione

Colorless solid (31%); ¹H NMR (DMSO-_(d6)) 2.64-2.81 (m, 3 H), 2.94 (dd,J=13.2, 4.4, 1 H), 3.71-3.78 (m, 1 H), 4.06 (s, 2 H), 4.59 (s, 2 H),7.27-7.40 (m, 10 H), 7.78 (d, J=2.2, 1 H). ¹³C NMR 37.4, 42.7, 50.9,52.7, 53.3, 127.2, 127.9, 128.2, 129.1, 129.2, 130.3, 137.9, 138.3,168.8, 171.2. LC/MS 5.14 min, [M+1]⁺ 309.

Preparative Example 20Tetrahydro-1,5-bis(phenylmethyl)-(5R)-1H-1,4-Diazepine-3,7-dione

Colorless solid (32%). LC/MS 5.14 min, [M+1]⁺ 309.

Preparative Examples 21-42

As illustrated below, the dione heterocycles were reduced to provide thenitrogen containing heterocycles.

Preparative Example 21 2(S)-N1 BOC-2-(2′-methylbenzyl)piperazine

1-Benzyl-3(S)-(2-methylbenzyl)-piperazine-2,5-dione (617 mg, 2 mmol) inTHF (10 mL) was treated with a 1N THF solution of LAH and heated atreflux for 6 h. The reaction was then cooled to room temperature andquenched dropwise with a 15% aqueous NaOH solution (0.5 mL) followed bywater (1 mL). The resulting mixture was treated with a small amount ofMgSO₄ and filtered through a pad of Celite® with the aid of EtOAc. Theorganic filtrate was then evaporated to an oil, dissolved in CH₂Cl₂ (5mL), and treated with TEA (560 uL, 4 mmol), and BOC anhydride (640 mg, 3mmol). The reaction was stirred for 3 h after which time and additionalportion of CH₂Cl₂ (10 mL) was added and the solution washed with asaturated aqueous solution of NH₄Cl (15 mL) followed by brine (2×10 mL).The organic portion was dried over MgSO₄, filtered and evaporated to anoil which was purified by silica gel flash chromatography with 15%EtOAc/hexanes as eluant to afford product as a colorless waxy solid (615mg, 81%) LC/MS 5.44 min, [M+1]⁺ 381.

The N1 -BOC N-4-benzylated solid (1.2 g, 3.15 mmol) was dissolved inMeOH (60 mL) and purged with nitrogen for 3 min followed by addition of10% palladium-on-carbon (50% water content, 500 mg). The reactionmixture was hydrogenated at ˜50-60 psi hydrogen for 6 h after which timethe mixture was filtered through a pad of Celite®. The organic filtratewas evaporated and dissolved in MeOH (10 mL) and filtered through anylon syringe filter (0.45 micron, 13 mm) to remove traces ofpalladium-on-carbon. The organic filtrate was again evaporated to afforda clear colorless oil (875 mg, 96%), ¹H NMR (CDCl₃) 1.33 (s,9 H), 2.39(s, 3 H), 2.67-2.91 (m, 4 H), 2.93-3.22 (m, 3 H), 3.95 (br d, J=12.5, 1H), 4.21 (br t, 1 H), 7.09-7.16 (m, 4 H). ¹³C NMR 19.7 (CH₃), 28.5(CH₃), 32.7 (CH₂), 33.2 (CH₂), 46.3 (CH₂), 47.6 (CH₂), 51.5 (CH), 79.7,126.1 (CH), 126.6 (CH), 126.9, 130.4 (CH), 130.5 (CH), 136.9, 137.5.LC/MS 4.09 min, [M+1]⁺ 291.

Preparative Example 22 2(R)-N1 BOC-2-(benzyl)-piperazine

Colorless waxy solid (89%, 96%); LC/MS 3.90 min, [M+1]⁺ 277.

Preparative Example 23 2(S)-N1 BOC-2-(3′-methylbenzyl)-piperazine

Colorless oil (84%, 92%); LC/MS 4.14 min, [M+1]⁺ 291.

Preparative Example 24 2(S)-N1 BOC-2-(4′-methylbenzyl)-piperazine

Colorless oil (86%, 94%); LC/MS 4.10 min, [M+1]⁺ 291.

Preparative Example 25 2(S)-N1 BOC-2-(2′-methoxylbenzyl)-piperazine

Colorless oil (83%, 94%); LC/MS 3.92 min, [M+1]⁺ 307.

Preparative Example 26 2(S)-N1 BOC-2-(3′-methoxylbenzyl)-piperazine

Colorless oil (47%, 83%); LC/MS 3.84 min, [M+1]⁺ 307.

Preparative Example 27 2(S)-N1 BOC-2-(4′-methoxylbenzyl)-piperazine

Colorless oil (85%, 88%); LC/MS 3.74 min, [M+1]⁺ 307.

Preparative Example 28 2(S)-N1 BOC-2-(4′-ethoxylbenzyl)-piperazine

Colorless oil (82%, 86%); LC/MS 4.41 min, [M+1]⁺ 321.

Preparative Example 29 2(S)-N1 BOC-2-(2-phenethyl)-piperazine

Colorless oil (83%, 96%); LC/MS 4.13 min, [M+1]⁺ 291.

Preparative Example 30 2(R)-N1 BOC-2(2-phenethyl)-piperazine

Colorless oil (85%, 96%); LC/MS 4.14 min, [M+1]⁺ 291.

Preparative Example 31 2(S)-N1 BOC-2-(3-phenylpropyl)-piperazine

Colorless oil (97%, 89%); LC/MS 4.32 min, [M+1]⁺ 305.

Preparative Example 32 2(S)-N1 BOC-2-(1′-naphthylmethyl)-piperazine

Colorless waxy solid (84%, 90%); LC/MS 4.35 min, [M+1]⁺ 327.

Preparative Example 33 2(S)-N1 BOC-2-(2′-naphthylmethyl)-piperazine

Colorless oil (73%, 98%); LC/MS 4.39 min, [M+1]⁺ 327.

Preparative Example 34 2(S)-N1 BOC-2-(4′-biphenylmethyl)-piperazine

Colorless waxy solid (66%, 99%); LC/MS 4.68 min, [M+1]⁺ 353.

Preparative Example 35 2(S)-N1 BOC-2-(diphenylmethyl)-piperazine

Colorless oil (35%, 92%); LC/MS 4.40 min, [M+1]⁺ 353.

Preparative Example 36 2(S)-N1 BOC-2-(cyclohexylmethyl)-piperazine

Colorless oil (87%, 89%); LC/MS 4.43 min, [M+1]⁺ 283.

Preparative Example 37 (S)-2-Benzyl-[1,4]diazepane-1-carboxylic acidtert-butyl ester

Colorless oil (75%, 93%); LC/MS 3.98 min, [M+1]⁺ 291.

Preparative Example 38 (R)-2-Benzyl-[1,4]diazepane-1-carboxylic acidtert-butyl ester

Colorless oil (65%, 92%); LC/MS 3.95 min, [M+1]⁺ 291.

Preparative Example 39 (S)-7-Benzyl-[1,4]diazepane-1-carboxylic acidtert-butyl ester

Colorless oil (73%, 88%); LC/MS 4.57 min, [M+1]⁺ 291.

Preparative Example 40 (R)-7-Benzyl-1-[1,4,]1diazepane-1-carboxylic acidtert-butyl ester

Colorless oil (71%, 88%); LC/MS 4.57 min, [M+1]⁺ 291.

Preparative Example 41 (2S,5S)-2-Benzyl-5-methyl-piperazine-1-carboxylicacid tert-butyl ester

Prepared from (3S, 6S)-6-methyl-,1,3-bis(phenylmethyl)-2,5-piperazinedione (CAS [561303-33-1]) Colorlessoil (66%, 92%); LC/MS 4.26 min, [M+1]⁺ 291.

Preparative Example 42 (2S,5R)-2-Benzyl-5-methyl-piperazine-1-carboxyicacid-tert-butyl ester

Prepared froth (3S, 6R)-6-methyl-,1,3-bis(phenylmethyl)-2,5-piperazinedione (CAS [850036-85-0]) Colorlessoil. (84%, 89%); LC/MS 4.46 min, [M+1]⁺ 291.

Preparative Examples 43-48 Preparative Example 43 (R)-2-benzylmorpholine

The title compound was prepared from (S)-(2,3-epoxypropyl)benzene by themethod of D'Amigo, Lattanzio, Fantoni and Serv in Tetrahedron:Asymmetry, 1998, 9, 4021-4026:

Preparative Example 44 6R and 6S-(phenylmethyl)piperazinone

The title compound (6R)-isomer was prepared from N-Cbz-D-phenylalinal bythe method of DeLucca in US2003/0144277 Al describing the preparation of6S-(phenylmethyl) piperazinone (CAS [503186-95-6]) fromN-Cbz-L-phenylalanal. LC/MS 5.40 and 5.34 min, [M+1]⁺191 and 191.

Preparative Example 45 4-bromo-7-methoxy-spiro[benzofuran-2(3H),1′-cyclopentane](CAS [185244-55-7)

The title compound was prepared from 5-bromo-2-methoxybenzaldehyde bythe method of Van der Mey, Margaretha; et. al., Journal of MedicinalChemistry 2001, 44, 2523-2535.

Preparative Example 46 6-Bromo-1-cyclopentyl-3methyl-1H-indazole

A solution of 4-bromo-2-fluoro-N-methoxy-N-methyl-benzamide (CAS[801303-33-3]) (13.1 g, 50.0 mmol) in THF (50 mL) at −78 C was treatedwith a 3 M solution of methyl magnesium bromide in diethyl ether (16.7mL, 50 mmol) and allowed to warm with stirring to 0 C over a 2-3 hperiod, after which time the reaction mixture was quenched with a halfsaturated aqueous solution of NH₄Cl (100 mL) and EtOAc (200 mL). Themixture was separated and the organic component, washed with brine (2×50mL), dried over MgSO₄, filtered, and evaporated to an oil which waspurified by silica gel flash chromatography with 5% EtOAc/hexanes aseluant to afford 1-(4-bromo-2-fluorophenyl)-ethanone as a liquid (9.25g, 85%). The ethanone (2.17 g, 10 mmol) was then dissolved in ethanol(25 mL), treated with hydrazine hydrate (535 uL, 11 mmol), and heated atreflux for 8 h. The reaction mixture was then evaporated and purified bysilica gel flash chromatography with 30% then 60% EtOAc/hexanes aseluant to afford the hydrazone as a solid (2.29 g, 99%). The hydrazone(3.69 g, 16 mmol) was then treated with ethylene glycol (25 mL) andheated at 165° C. for 6 h after which time the cooled reaction mixturewas poured onto water (100 mL). The aqueous mixture was neutralized,with rapid stirring, using a small amount of an aqueous saturatedsolution of NaHCO₃ to afford a pale yellow precipitate. The solids werefiltered, washed with water, and air dried to afford cyclized indazoleproduct (2.62 g, 78%). The indazole (2.32 g, 11 mmol) was then dissolvedin anhydrous DMF (50 mL) and treated with a 60% dispersion of sodiumhydride in mineral oil (420 mg, 10.5 mmol). After 30 min of stirring,cyclopentyl bromide (1.53 mL, 14.3 mmol) was added and the reactionstirred for 24 h. The reaction mixture was quenched by pouring ontowater (500 mL) which was neutralized with a small portion of a 1 Naqueous HCl solution and extracted with EtOAc (2×200 mL, then 100 mL).The combined organic extracts were dried over MgSO₄, filtered, andevaporated to an oil, which was purified by silica gel flashchromatography with 25% then 80% EtOAc/hexanes as eluant to affordproduct as a clear yellow tinted oil (1.65 g, 54%). ¹H NMR (CDCl₃)1.68-1.78 (m, 2 H), 1.93-2.01 (m, 2 H), 2.08-2.16 (m, 4 H), 2.54 (s, 3H), 4.77-4.87 (m, 1 H), 7.18 (dd, J=8.4, 1.5, 1 H), 7.32 (dd, J=8.4,0.7, 1 H), 7.55 (d, J=1.5, 1 H). ¹³C NMR 12.1 (CH₃), 24.7 (CH₂), 32.2(CH₂), 59.5 (CH), 112.2 (CH), 120.5, 121.8 (CH), 122.5, 123.2 (CH),141.1, 141.4. LC/MS 7.71 min, [M+1]⁺ 281.

Preparative Example 47 6-Bromo-1-cyclopentyl-3-ethyl-1H-indazole, CAS[199172-02-N

The title compound was prepared by the method outlined for PreparativeExample 46 using a 25% wt THF solution of ethyl magnesium bromide andstirring the resulting solution for 24 h at 0° C. in lieu of methylmagnesium bromide and a 2-3 h period at 0° C. LC/MS 8.14 min, [M+1]⁺295.

Preparative Example 48

2(S)-N1 BOC-2-(benzyl)-piperazine CAS [169447-86-3], 2(R) -N1BOC-2-(phenyl)-piperazine CAS [859518-32-4], 2(S)-N1BOC-2-(isobutyl)-piperazine, 2(R)-N1 BOC-2-(isopropyl)-piperazine, and2(R)-N1 BOC-2-(3-indolylmethyl)-piperazine were purchased from CNHTechnologies, Inc (Woburn, Mass., USA).

Examples 1-73

The following compounds of the invention were prepared as illustratedbelow.

Example 1 Preparation of Compound 49,(S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-(2-methyl-benzyl)-piperazine

A solution of 2(S)-N1 BOC-2-(2′-methylbenzyl)piperazine (290 mg, 1.0mmol) in anhydrous toluene (2 mL) was treated with3-(cyclopentoxy)-4-methoxy-bromobenzene (271 mg, 1.0 mmol), sodiumtert-butoxide (96 mg, 1.0 mmol),2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (56 mg, 0.06mmol), and tris(dibenzylideneacetone)dipalladium (14 mg, 0.015 mol). Theresulting mixture was heated under nitrogen atmosphere at 100-105° C.for 5 h. The crude reaction mixture was then, diluted with EtOAc (10mL), washed with water (10 mL) followed by a saturated aqueous NaHCO₃solution (10 mL), and brine (10 mL). The organic portion was then driedover MgSO₄, filtered and evaporated to an oil, which was purified bysilica gel flash chromatography with 15% EtOAc/hexanes as eluant toafford product as an oil (215 mg, 45%). LC/MS 8.63 min, [M+1]⁺ 481.

The purified coupled product (215 mg, 0.447 mmol) was then treated witha 4N solution of hydrogen chloride in 1,4-dioxane and stirred for 2. Thereaction was then evaporated to a colorless solid, suspended in EtOAc(1.0 mL), and washed with a saturated aqueous K₂CO₃ solution (3 mL)followed by brine (3 mL). The organic portion was then dried over MgSO₄,filtered, and evaporated to a burgundy colored oil (127 mg, 75%). ¹H NMR(CDCl₃) 1.57-1.61 (m, 2 H), 1.79-1.92 (m, 6 H), 2.36 (s, 3 H), 2.49-2.56(m, 1 H), 2.70-2.87 (m, 2 H), 2.96 (td, J=11.2, 2.9, 1 H), 3.08-3.16 (m,2 H), 3.35-3.39 (m, 2 H), 3.78 (s, 3 H), 4.71-4.74 (m, 1 H), 6.43 (dd,8.7; 2.6, 1 H), 6.53 (d, J=2.9, 1 H) 6.78 (d, J=8.8, 1 H), 7.11-7.26 (m,4 H) ¹³C NMR 19.8 (CH₃), 24.2 (CH₂), 32.97 (CH₂), 37.9 (CH₂), 46.0(CH₂), 51.3 (CH₂), 55.3 (CH), 56.8 (CH₃), 56.8 (CH₂), 80.6, (CH), 106.8(CH), 108.6 (CH), 113.3 (CH), 126.1 (CH), 126.8 (CH), 130.2 (CH), 130.7(CH), 136.4, 136.7, 144.8, 146.5, 148.4. LC/MS 5.03 min, [M+1]⁺ 381.

Example 2 Preparation of Compound 50,(S)-3-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine

The title compound was prepared by the method outlined for Example 1using 2(S)-N1 BOC-2-(benzyl)-piperazine CAS [169447-86-3] as aminecomponent. Oils (68 and 90%). LC/MS 8.46 and 5.05 min, [M+1]⁺ 467 and367.

Example 3 Preparation of Compound 51, (2S,5S)-5-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-2-methyl-piperazine

Prepared by the method outlined for Example 1 using(2S,5S)-2-Benzyl-5-methyl-piperazine-1-carboxylic acid tert-butyl esteras piperazine component. Foam and oil (33 and 96%). LC/MS 8.48 and 5.06min, [M+1]⁺ 481 and 381.

Example 4 Preparation of Compound 52, (2 R,5S)-5-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-2-methyl-piperazine

Prepared by the method outlined for Example 1 using(2S,5R)-2-Benzyl-5-methyl-piperazine-1-carboxylic acid tert-butyl esteras piperazine component. Foam and oil (61 and 86%). LC/MS 8.57 and 5.03min, [M+1]⁺ 481 and 381.

Example 5 Preparation of Compound 53,(R)-6-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-2-one

Prepared by the coupling method outlined for Example 1 using6R-(phenylmethyl) piperazinone as amine component to afford coupledproduct as a colorless solid (10%). ¹H NMR (CDCl₃) 1.59-1.62 (m, 2 H),1.77-1.90 (m, 6 H), 2.82 (dd, J=13.4, 8.1, 1 H), 2.98 (dd, J=13.6, 6.4,1 H), 3.07 (dd, J=12.5, 7.0, 1 H), 3.44 (dd, J=12.5, 3.7, 1 H), 3.77(obs dd, 1 H), 3.80 (s, 3 H), 4.70-4.74 (m, 1 H), 6.25 (br s, 1 H), 6.39(dd, 8.6, 2.6, 1 H), 6.48 (d, J=2.6, 1 H), 6.80 (d, J=8.8, 1 H),7.20-7.38 (m, 5 H). LC/MS 6.26, [M+1]⁺ 381.

Example 6 Preparation of Compound 54,(S)-6-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-2-one

Prepared by the coupling method outlined in Example 1, using6S-(phenylmethyl) piperazinone (CAS [503186-95-6]) as the aminecomponent. Colorless solid (11%). LC/MS 6.39, [M+1]⁺ 381.

Example 7 Preparation of Compound 55,(R)-3-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine

(R)-6-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-2-one(Compound 53) (365 mg, 0.959 mmol) was dissolved in THF (10 mL), cooledto 0° C., and treated with solid lithium aluminum hydride (73 mg, 1.92mmol). The reaction mixture was heated at 60° C. for 3 hr then cooled to0° C. and quenched with EtOAc (2 mL) and a 1 N aqueous solution of NaOH(2 mL). The reaction was filtered with the aid of EtOAc, dried overMgSO₄, filtered, and evaporated to an oil, which was purified by silicagel flash chromatography with 5% Me0H/CH₂Cl₂ as eluant to afford productas a brown colored oil (228 mg, 65%). LC/MS 5.12 min, [M+1]⁺ 367.

Example 8 Preparation of Compound 56,(S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-(3-methyl-benzyl)-piperazine

Prepared by the method outlined for Example 1 using 2(S)-N1BOC-2-(3′methylbenzyl)-piperazine as piperazine component. Oils (38 and92%). LC/MS 8.67 and 5.18 min, [M+1]⁺ 481 and 381.

Example 9 Preparation of Compound 57,(S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-(4-methyl-benzyl)-piperazine

Prepared by the method outlined for Example 1 using 2(S)-N1BOC-2-(4′-methylbenzyl)-piperazine as piperazine component. Oils (34 and88%). LC/MS 8.68 and 5.07 min, [M+1]⁺ 481 and 381.

Example 10 Preparation of Compound 58,(S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-(2-methoxy-benzyl)-piperazine

Prepared by the method outlined for Example 1 using 2(S)-N1BOC-2-(2′-methoxybenzyl)-piperazine as piperazine component. Oils (56and 80%). LC/MS 8.29 and 5.03 min, [M+1]⁺ 497 and 397.

Example 11 Preparation of Compound 59,(S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-(3-methoxy-benzyl)-piperazine

Prepared by the method outlined for Example 1 using (S)-N1BOC-2-(3′-methoxybenzyl)-piperazine as piperazine component. Oils (42and 92%). LC/MS 8.19 and 4.83 min, [M+1]⁺ 497 and 397.

Example 12 Preparation of Compound 60,(S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-(4-methoxy-benzyl)-piperazine

Prepared by the method outlined for Example 1 using (S)-N1BOC-2-(4′-methoxybenzyl)-piperazine as piperazine component. Oils (64and 85%). LC/MS 8.15 and 4.81 min, [M+1]⁺ ⁴⁹⁷ and 397.

Example 13 Preparation of Compound 61,(S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-(4-ethoxy-benzyl)-piperazine

Prepared by the method outlined for Example 1 using (S)-N1BOC-2-(4′-ethoxybenzyl)-piperazine as piperazine component. Oils (67 and75%). LC/MS 8.44 and 4.96 min, [M+1]⁺ 511 and 411.

Example 14 Preparation of Compound 62,(S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-phenethyl-piperazine

Prepared by the method outlined for Example 1 using 2(S)-N1BOC-2-(2-phenethyl)-piperazine as piperazine component. Oils (44 and91%). LC/MS 8.49 and 4.91 min, [M+1]⁺ 481 and 381.

Example 15 Preparation of Compound 63,(R)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-phenethyl-piperazine

Prepared by the method outlined for Example 1 using 2(R)-N1BOC-2-(2-phenethyl)-piperazine as piperazine component. Oils (51 and86%). LC/MS 8.49 and 4.96 [M+1]⁺ 481 and 381.

Example 16 Preparation of Compound 64,(S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-(3-phenyl-propyl)-piperazine

Prepared by the method outlined for Example 1 using 2(S)-N1BOC-2-(3-phenylpropyl)-piperazine as piperazine component. Oils (38 and91%). LC/MS 8.71 and 5.22 min, [M+1]⁺ 495 and 395.

Example 17 Preparation of Compound 65,(S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-naphthalen-1-ylmethyl-piperazine

Prepared by the method outlined for Example 1 using 2(S)-N1BOC-2-(1′-naphthylmethyl)-piperazine as piperazine component. Oils (42and 96%). LC/MS 8.81 and 5.30 min, [M+1]⁺ 517 and 417.

Example 18 Preparation of Compound 66,(S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-naphthalen-2-ylmethyl-piperazine

Prepared by the method outlined for Example 1 using 2(S)-N1BOC-2-(2′-naphthylmethyl)-piperazine as piperazine component. Oils (43and 89%). LC/MS 8.78 and 5.29 min, [M+1]⁺ 517 and 417.

Example 19 Preparation of Compound 67,(S)-3-Biphenyl-4-ylmethyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine

Prepared by the method outlined for Example 1 using 2(S)-N1BOC-2-(4′-biphenylmethyl)-piperazine as piperazine component. Oils (59and 94%). LC/MS 9.03 and 5.52 min, [M+1]⁺ 543 and 443.

Example 20 Preparation of Compound 68,(S)-3-Benzhydtyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine

Prepared by the method outlined for Example 1 using 2(S)-N1BOC-2-(diphenylmethyl)-piperazine as piperazine component. Oils (28. and100%). LC/MS 8.58 and 5.39 min, [M+1]⁺ 543 and 443.

Example 21 Preparation of Compound 69,(R)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-phenyl-piperazine

Prepared by the method outlined for Example 1 using 2(R)-N1BOC-2-(phenyl)-piperazine as piperazine component. Foam and oil (66 and86%). LC/MS 8.09 and 4.78 min, [M+1]⁺ 453 and 353.

Example 22 Preparation of Compound 70,(S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-isopropyl-piperazine

Prepared by the method outlined for Example 1 using 2(R)-N1BOC-2-(isopropyl)-piperazine as piperazine component. Oils (54 and 71%).LC/MS 8.32 and 4.62 min, [M+1]⁺ 419 and 319.

Example 23 Preparation of Compound 71,(S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-isobutyl-piperazine

Prepared by the method outlined for the Example 1 using 2(R)-N1BOC-2-(isobutyl) -piperazine as piperazine component Oils (63 and 94%)LC/MS 841 and 458 min, [M+1]⁺433 and 333.

Example 24 Preparation of Compound 72,(S)-3-Cyclohexylmethyl-1-(3-cyclopentyloxy4-methoxy-phenyl)-piperazine

Prepared by the method outlined for Example 1 using 2(S)-N1BOC-2-(cyclohexylmethyl)-piperazine as piperazine component. Oils (49and 88%). LC/MS 9.36 and 5.30 min, [M+1]⁺ 473 and 373.

Example 25 Preparation of Compound 73,3-[(S)-4-(3-Cyclopentyloxy-4-methoxy-phenyl)-piperazin-2-ylmethyli-1H-indole

Prepared by the method outlined for Example 1 using 2(R)-N1BOC-2-(3-indolylmethyl)-piperazine as piperazine component. The BOCprotected intermediate was chromatographically purified with a 2.5% then7.5% Me0H/CH₂Cl₂ solvent system. Oils (25 and 92%). LC/MS 5.72 and 455min, [M+1]⁺ 506 and 406.

Example 26 Preparation of Preparation of Compound 74,6S9-3-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-[1,4]diazepane

Prepared by the method outlined for Example 1 using(S)-2-Benzyl-[1,4]diazepane-1-carboxylic acid tert-butyl ester aspiperazine component. Oils (42 and 92%). LC/MS 7.99 and 5.07 min, [M+1]⁺481 and 381.

Example 27 Preparation of Compound 75,(R)-3-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-11,4]diazepane

Prepared by the method outlined for Example 1 using(R)-2-Benzyl-[1,4]diazepane1-carboxylic acid, tert-butyl ester aspiperazine component. Oils (29 and 93%). LC/MS 7.96 and 5.03 min, [M+1]⁺481 and 381.

Example 28 Preparation of Preparation of Compound 76,(S)-5-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl) [1,4]diazepane

Prepared by the method outlined for Example 1 using (S)-7-Benzyl[1,4]diazepane-1-carboxylic acid, tert-butyl ester as piperazinecomponent. Oils (23 and 99%). LC/MS 7.42 and 4.91 min, [M+1]⁺ 481 and381.

Example 29 Preparation of Compound 77,(R)-5-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-[1,4]diazepane

Prepared by the method outlined for Example 1 using(R)-7-Benzyl-[1,4]diazepane-1-carboxylic acid, tert-butyl ester aspiperazine component. Oils (16 and 91%). LC/MS 7.43 and 4.89 min, [M+1]⁺481 and 381.

Example 30 Preparation of Compound 78,1-(3-Cyclopentyloxy-4-methoxy-phenyl)-piperazine

Prepared by the method outlined for Example 1 using N-BOC-piperazine aspiperazine component. Oils (65% for two steps). LC/MS 4.11 min, [M+1]⁺277.

Example 31 Preparation of Compound 79,(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-morpholine

Prepared by the coupling method outlined for Example 1 using2(S)-2-(benzyl)-morpholine as the amine component. Oil (29%). LC/MS 7.27min, [M+1]⁺ 368.

Example 32 Preparation of Compound 80, 4-[(S)-3-benzyl-1piperziny]-7-methoxy-spiro[benzofuran-2(3 H), 1′-cyclopentane]

Prepared by the method outlined for Example 1 using4-bromo-7-methoxy-spiro[benzofuran-2(3 H), 1′-cyclopentane] (CAS[185244-55-7]) as the aryl halide and 2(S)-N1 BOC-2-(benzyl)-piperazineas the amine component. Oil (79% for two steps). LC/MS: 5.02 min, [M+1]⁺379.

Example 33 Preparation of Compound 81,6-((S)-3-Benzyl-piperazin-1-yl)-1-cyclopentyl-3-methyl-1H-indazole

Prepared by the method outlined for Example 1 using6-bromo-1-cyclopentyl-3-methyl-1H-indazole as the aryl halide and2(S)-N1 BOC-2-(benzyl)-piperazine as the amine component. Oils (81 and76%). LC/MS 5.13 min, [M+1]⁺ 375.

Example 34 Preparation of Compound 82,1-Cyclopentyl-3-ethyl-6-piperazin-1-yl-1H-indazole

Prepared by the method outlined for Example 1 using6-bromo-1-cyclopentyl-3-ethyl-1H-indazole (CAS [199172-02-6]) as thearyl halide and N BOC-piperazine as the amine component. Oil and gum(88% for two steps). LC/MS 4.56 min, [M+1]⁺ 299.

Example 35 Preparation of Compound 83,64(S)-3-Benzyl-piperazin-1-yl)-1-cyclopentyl-3-ethyl-1H-indazole

Prepared by the method outlined for Example 1 using6-bromo-1-cyclopentyl-3-ethyl-1H-indazole (CAS [199172-02-6]) as thearyl halide and 2(S)-N1 BOC-2-(benzyl)-piperazine as the aminecomponent. Oil (86 and 90%). LC/MS 5.28 min, [M+1]⁺ 389.

Example 36 Preparation of Compound 84,(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-1-methyl-piperazine

A solution of(S)-3-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine (Example2) (73 mg, 0.2 mmol) in CH₂Cl₂ (5 mL) was treated with a 37% aqueousformaldehyde solution (16.4 uL, 0.22 mmol) and stirred for 5 min afterwhich time solid, sodium triacetoxyborohydride (64 mg, 0.3 mmol) wasadded. The suspension was then stirred for 3 hr then quenched with asaturated aqueous NaHCO₃ solution (2 mL). The organic component wasseparated, dried over MgSO₄, filtered, and evaporated to an oil whichwas purified by silica gel flash chromatography with 5% MeOH/CH₂Cl₂ aseluant to afford product as a burgundy oil (69 mg, 91%). ¹H NMR (CDCl₃)1.54-1.61 (m, 2 H), 1.77-1.85 (m, 6 H), 2.57 (s, 3 H), 2.60-2.67 (m, 3H), 3.02-3.13 (m, 3 H), 3.22-3.32 (m, 2 H), 3.76 (s, 3 H), 4.59-4.62 (m,1 H), 3.76 (s, 3 H), 4.59-4.62 (m, 1 H), 6.30 (dd, J=8.6, 2.9, 1 H),6.35 (d, J=8.6, 1 H), 7.20-7.33 (m, 5 H). ¹³C NMR 24.2 (CH₂), 33.0(CH₂), 36.3 (CH₂), 42.9(CH₃), 50.2 (CH₂), 55.0 (CH₂), 55.1 (CH₂), 56.8(CH₃), 63.7 (CH), 80.4 (CH), 106.2 (CH), 107.8(CH), 113.2(CH), 126.4(CH) 128.6, 129.5 (CH), 139.0 (CH), 144.5, 146.1, 148.4. LC/MS 5.10 min,[M+1]⁺ 381.

Example 37 Preparation of Compound 85,(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-1-ethyl-piperazine

Prepared by the method outlined for Example 36 using acetaldehyde as thealdehyde component. Oil (84%). LC/MS 4.73 min, [M+1]⁺ 395.

Example 38 Preparation of Compound 86,(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-1-propyl-piperazine

Prepared by the method outlined for Example 36 using propionaldehyde asthe aldehyde component. Oil (95%). LC/MS 4.80 min, [M+1]⁺ 409.

Example 39 Preparation of Compound 87,(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-1-benzyl-piperazine

Prepared by the method outlined for Example 36 using benzaldehyde as thealdehyde component. Oil (50%). LC/MS 5.43 min, [M+1]⁺ 457.

Example 40 Preparation of Compound 88,(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-1-pyridin-2-ylmethyl-piperazine

Prepared by the method outlined for Example 36 using2-pyridinecarboxaldehyde as the aldehyde component. Oil (44%). LC/MS5.38 min, [M+1]⁺ 458.

Example 41 Preparation of Compound 89,(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-1-pyridin-3-ylmethyl-piperazine

Prepared by the method outlined for Example 36 using3-pyridinecarboxaldehyde as the aldehyde component. Oil (57%): LC/MS5.07 min, [M+1]⁺ 458.

Example 42 Preparation of Compound 90,(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-1-pyridin-4-ylmethyl-piperazine

Prepared by the method outlined for Example 36 using4-pyridinecarboxaldehyde as the aldehyde component. Oil (44%). LC/MS5.21 min, [M+1]⁺ 458.

Example 43 Preparation of Compound 91,(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-1-(3H-imidazol-4-ylmethyl)-piperazine

Prepared by the method outlined for Example 36 using1-tritylimidazole-4-carboxaldehyde as the aldehyde component. Oil (69%)LC/MS 6.25 min, [M+1]⁺ 689. The trityl protected intermediate wasdeprotected by dissolving the intermediate (90 mg, 0.1345 mmol) inCH₂Cl₂ (0.5 mL) which was treated with triethylsilane (0.5 mL) followedby trifluoroacetic acid (1.0 mL). The reaction mixture was stirred for 2h then evaporated to a residue which was triturated with a 10%EtOAc/hexane solution (4×1 mL). The residue was then partitioned betweenEtOAc (1 mL) and a saturated aqueous K₂CO₃ solution (0.5 mL). Theorganic component was separated, dried over MgSO₄, filtered, andevaporated to afford product as a foam (50 mg, 83%). LC/MS 4.50 min,[M+1]⁺ 447.

Example 44 Preparation of Compound 92,(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-1-(1H-imidazol-2-ylmethyl)-piperazine

Prepared by the method outlined for Example 43 using1-tritylimidazole-2-carboxaldehyde as the aldehyde component. Oil andfoam (63 and 75%). LC/MS 6.20 and 4.77 min, [M+1]⁺ 689 and 447.

Example 45 Preparation of Compound Compound 93,(S)-2-Benzyl-4-(3-cyclopentyloxy4-methoxy-phenyl)-1-methanesulfonyl-piperazine

A solution of the bis-hydrochloride salt of(S)-3-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine (Example2) (50 mg, 0.114 mmol) in pyridine (1 mL) was treated withmethanesulfonyl chloride (26 μL, 0.341 mmol) and stirred at roomtemperature for 16 h. The reaction mixture was evaporated andpartitioned between EtOAc (2 mL) and a saturated aqueous NaHCO₃ solution(2 mL). The organic component was separated, dried over MgSO₄, filtered,and evaporated to an oil which was purified by silica gel flashchromatography with 30% then 40% EtOAc/hexane as eluant to affordproduct as an oil (46 mg, 91%). ¹H NMR (CDCl₃) 1.60-1.62 (M, 2 H),1.84-1.87 (m, 4 H), 1.90-2.04 (m, 2 H), 2.55 (s, 3 H), 2.76-2.80 (m, 2H), 3.19-3.56 (m, 5 H), 3.77 (m, 1 H), 3.80 (s, 3 H), 4.30 (br t, 1 H),4.71 (m, 1 H), 6.42 (br d, J=8.1, 1 H),6.48 (br s, 1 H), 6.78 (d, J=8.6,1 H), 7.23-7.36 (m, 5 H). LC/MS 7.25 min, [M+1]⁺ 445.

Example 46 Preparation of Compound Compound 94,(S)-2-Benzyl-4-(3-cyclopentyloxy4-methoxy-phenyl)-1-ethanesulfonyl-piperazine

Prepared by the method outlined for Example 45 using ethanesulfonylchloride as the sulfonyl chloride component. Oil (17%). LC/MS 7.41 min,[M+1]⁺ 459.

Example 47 Preparation of Compound 95,(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-1-benzylsulfonyl-piperazine

Prepared by the method outlined for Example 45 using benzylsulfonylchloride as the sulfonyl chloride component. Oil (6%). LC/MS 7.82 min,[M+1]⁺ 521.

Example 48 Preparation of Compound 96,1-1-(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-ylJ-ethanone

Prepared by the method outlined for Example 45 using acetic anhydride asreagent. Oil (97%). LC/MS 6.88 min, [M+1]⁺ 409.

Example 49 Preparation of Compound 97,(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine-1-carboxylicacid ethylamide

A solution of(S)-3-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine (Example2) (73 mg, 0.2 mmol) in CH₂Cl₂ (0.5 mL) at 0° C. was treated with ethylisocyanate (19 μL, 0.24 mmol) and stirred for 1 h, then evaporated andthe residue purified by silica gel flash chromatography with 50% then75% EtOAc/hexane as eluant to afford product as a foam (60 mg, 69%) ¹HNMR (CDCI₃) 1.04 (t, J=7.2, 3 H), (m, 2 H), 1.79-1.90 (m, 3 H),1.91-1.96 (m, 2 H), 2.67-2.75 (m, 2 H), 3.00-3.43(m, 7 H), 3.79(s, 3 H),3.93 (br d, J=12.5, 1 H), 4.13-4.27 (m, 2 H), 4.70-4.73 (m, 1 H), 6.40(br d, J=7.5; 1 H), 6.49 (br s, 1 H), 6.78 (d, J 8.8, 1 H), 7.22-7.35(m, 5 H): LC/MS 6.86 min, [M+1]⁺ 438.

Example 50 Preparation of Compound 98,(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl-piperazine-1-carboxylicacid ethyl ester

A solution of (S)-3-Benzyl-1-cyclopentyloxy-4-methoxy-phenyl)-piperazine(Example 2) (73 mg, 0.2 mmol) in THF (0.5 mL) at room temperature wastreated with triethyl amine (28.4, 0.2 mmol), followed by ethylchloroformate (19 μL, 0.2 mmol). The reaction mixture was stirred for 2h then diluted with EtOAc (2 mL) followed by a saturate aqueous NaHCO₃solution (1 mL). The organic phase was isolated and further washed withan additional portion of a saturated aqueous NaHCO₃ solution (1 mL)followed by a brine solution (1 mL). The organic component was driedover MgSO₄, filtered, and evaporated to an oil which was purified bysilica gel flash chromatography with 10% then 30% EtOAc/hexane as eluantto afford product as an oil (30 mg, 34%) ¹H NMR (CDCl₃) 1.25 (t, J=7.2,3 H), 1.60-1.65 (m, 2 H), 1.79-1.89 (m, 3 H), 1.92-2.00 (m, 2 H),2.60-2.72 (m, 2 H), 2.95 (dd, J=12.9, 4.8, 1 H), 3.20-3.28 (m, 2 H),3.33-3.42 (m, 2 H), 3.79 (s, 3 H), 4.08-4.13 (m, 3 H), 4.40 (br s, 1 H),4.69-4.72 (m, 1 H), 6.39 (dd, J=8.6, 2.4, 1 H), 6.47 (s, 1 H), 6.77 (d,J=8.6, 1 H), 7.22-7.34 (m, 5 H). LC/MS 7.81 min, [M+1]⁺ 439.

Example 51 Preparation of Compound 99,1-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-2-hydroxy-ethanone

A solution of(S)-3-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine (Example2) (73 mg, 0.2 mmol) in THF (1.5 mL) at room temperature was treatedwith triethylamine (42 μL, 0.3 mmol) followed by benzyloxyacetylchloride (19 μL, 0.2 mmol). The reaction mixture was stirred for 2 hthen diluted with EtOAc (2 mL) and water (2 mL). The organic phase wasisolated and further washed with an additional portion of a water (2 mL)followed by a brine solution (2 mL). The organic component was driedover MgSO₄, filtered, and evaporated to an oil which was purified bysilica gel flash chromatography with 20% then 40% EtOAc/hexane as eluantto afford coupled product as an oil (69 mg, 67%). LC/MS 7.64 min, [M+1]⁺515. The intermediate benzyloxy ether (60 mg,0.117 mmol) was dissolvedin MeOH (20 mL), purged with a stream of nitrogen, treated with 20% Pd/C(140 mg, 50% water content), and hydrogenated under 40 psi pressure ofhydrogen for 4 h. The crude reaction mixture was then purged withnitrogen, filtered, evaporated, and purified by silica gel flashchromatography with 40% then 75% EtOAc/hexane as eluant to affordproduct as an oil (9 mg, 18%). LC/MS 6.55 min, [M+1]⁺ 425.

Example 52 Preparation of Compound 100,2-Amino-1-[(S)-2-benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-ethanone,hydrochloride salt

A solution of(S)-3-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine (Example2) (73 mg, 0.2 mmol) and BOC-glycine (35 mg, 0.2 mmol) in DMF (1.0 mL)at room temperature was treated with diisopropylethylamine (35 μL, 0.2mmol) followed by HATU (84 mg, 0.22 mmol). The reaction mixture wasstirred for 2 h then partitioned between EtOAc (10 mL) and a saturatedaqueous NaHCO₃ solution (10 mL). The organic component was isolated andfurther washed with brine (10 mL) then dried over MgSO₄, filtered, andevaporated to an oil which was purified by silica gel flashchromatography with 40% EtOAc/hexane as eluant to afford BOC-containingcoupled product as a foam (85 mg, 81%). LC/MS 7.46 min, [M+1]⁺ 524. TheBOC-protected intermediate was dissolved in a 4 N solution of hydrogenchloride in dioxane, and stirred for 2 h then evaporated to a solidwhich was filtered and washed with diethyl ether to afford product as acolorless solid (42 mg, 49% based on trihydrochloride salt). LC/MS 4.66min, [M+1]⁺ 424.

Example 53 Preparation of Compound 101,1-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-2-methylamino-ethanone,hydrochloride salt

Prepared by the method outlined for Example 52 using BOC-sarcosine asthe acid coupling component. Foam and solid (74 and 86%, based ontrihydrochloride salt). LC/MS 7.46 and 4.72 min, [M+1]⁺ 539 and 438.

Example 54 Preparation of Compound 102,4-[(1-((S)-3-benzyl-4-piperazin-1-yl-2-hydroxy-ethanone)]-7-methoxy-spiro[benzofuran-2(3H), 1′-cyclopentane]

Prepared by the method outlined for Example 51 using compound 80(Example 32) as the amine coupling component. Oils (67 and 37%). LC/MS7.60 and 6.68 min, [M+1]⁺ 527 and 437.

Example 55 Preparation of Compound 103,1-[(S)-2-Benzyl-4-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-piperazin-1-yl]-2-hydroxy-ethanone

Prepared by the method outlined for Example 51 using6-((S)-3-Benzyl-piperazin-1-yl)-1-cyclopentyl-3-ethyl-1H-indazole(Example 35) as the amine coupling component. Oils (73 and 49%). LC/MS8.03 and 7.12 min, [M+1]⁺ 537 and 447.

Example 56 Preparation of Compound 104,2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-acetamide

A solution of the bishydrochloride salt of(S)-3-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine (Example2) (110 mg, 0.25 mmol) in THF (2 mL) at room temperature was treatedwith diisopropylethylamine (165 μL, 1.0 mmol) followed by2-bromoacetamide (42 mg, 0.3 mmol). The reaction mixture was heated at50° C. for 8 h and an additional amount of bromide (42 mg, 0.3 mmol)then added. The reaction mixture was then stirred for an additional 16 hat room temperature and evaporated. The crude reaction was thenpartitioned between EtOAc (3 mL) and a saturated aqueous NaHCO₃ solution(3 mL). The organic phase was isolated and further washed with anadditional portion of a saturated aqueous NaHCO₃ solution (3 mL) andbrine (2×3 mL).

The organic component was dried over MgSO₄, filtered, and evaporated toan oil which was purified by silica gel flash chromatography with 80%EtOAc/hexane then 5% MeOH/EtOAc as eluant to afford product as an oil(23 mg, 22%). LC/MS 5.09 min, [M+1]⁺ 424.

Example 57 Preparation of Compound 105,[(S)-2-Benzyl4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-aceticacid methyl ester

A solution of the bishydrochloride salt of(S)-3-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine (Example2) (110 mg, 0.25 mmol) in THF (2 mL) at room temperature was treatedwith diisopropylethylamine (165 μL, 1.0 mmol) followed by 2-bromomethylacetate (95 μL, 1.0 mmol). The reaction mixture was stirred for 16h at room temperature and evaporated. The crude reaction was thenpartitioned between EtOAc (3 mL) and a saturated aqueous NaHCO₃ solution(1 mL). The organic phase was isolated and further washed with anadditional portion of a saturated aqueous NaHCO₃ solution (2×2 mL) andbrine (2×2 mL). The organic component was dried over MgSO₄, filtered,and evaporated to an oil, which was purified by silica gel flashchromatography with 25% EtOAc/hexane as eluant to afford product as anoil (82 mg, 75%). ¹H NMR (CDCl₃) 1.56-1.58 (m, 2 H), 1.78-2.04 (m, 6 H),2.66-2.75 (m, 2 H), 2.90-3.14 (m, 6 H), 31.9-3.24 (m, 1 H), 3.58 (s, 2H), 3.76 (s, 3 H), 3.76 (s, 3 H), 4.62 (m, 1 H), 6.34 (dd, J=8.6, 2.6, 1H), 6.73 (d, J=8.8, 1 H), 7.18-7.32 (m, 5 H), ¹³C NMR 24.2 (CH₂), 33.0(CH₂), 35.2 (CH₂), 50.2 (CH₂), 51.5 (CH₃), 51.9 (CH₂), 55.0 (CH2), 55.5(CH₂), 56.8 (CH₃), 60.5 (CH), 76.8 (CH), 106.4 (CH), 108.0 (CH), 113.3(CH), 126.5 (CH) 128.7 (CH), 129.5 (CH), 139.0, 144.6, 146.2, 148.4,171.2. LC/MS 5.74 min, [M+1]⁺ 439.

Example 58 Preparation of Compound 106,2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-ethanol

A solution of[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1yl]-aceticacid methyl ester (Example 57) (110 mg, 0.25 mmol) in THF (2 mL) at roomtemperature was treated with a 1 N THF solution of lithium aluminumhydride (750 μL, 0.75 mmol) and allowed to stir for 12 h. The reactionmixture was quenched with an aqueous 15% NaOH solution (250 μL) followedby water (250 μL) and THF (2 mL) the reaction mixture was then treatedwith MgSO₄, filtered, and evaporated. The residue was then dissolved inEtOAc (3 mL), retreated with MgSO₄, filtered, and evaporated to affordproduct as an oil (75 mg, 73%). ¹H NMR (CDCl₃) 1.58-1.62 (m, 2 H),1.67-1.88 (m, 6 H), 2.74-3.22 (m, 12 H), 3.65-3.76 (m, 2 H), 3.78 (s, 3H), 4.64-4.67 (m, 1 H), 6.34 (dd, J=8.6, 2.9, 1 H), 6.40 (d, J=2.6, 1H), 6.75 (d, J=8.6, 1 H), 7.20-7.33 (m, 5 H). ¹³C NMR 24.2 (CH₂), 33.0(CH₂), 33.0 (CH₂), 48.4 (CH₂), 49.7 (CH₂), 53.9 (CH₂), 55.5 (CH₂), 56.9(CH₃), 58.1 (CH₂), 61.6 (CH), 80.5 (CH), 106.5 (CH), 108.1 (CH), 113.4(CH), 126.5 (CH) 128.8 (CH), 129.5 (CH), 139.6, 144.7, 146.5, 148.5.LC/MS 4.81 min, [M+1]⁺ 411.

Example 59 Preparation of Compound 107,[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-aceticacid

A solution of[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-aceticacid methyl ester (Example 57) (342 mg, 0.78 mmol) in THF (5 mL) at roomtemperature was treated with an aqueous solution (1 mL) containinglithium hydroxide monohydrate (36 mg, 0.858 mmol). The reaction mixturewas allowed to stir for 2 h and then evaporated to a small volume. Thereaction mixture was then dissolved in water (5 mL) and the pH adjustedto ˜7 with 1 N HCl to precipitate product. The precipitate was thentriturated with water (2×5 mL) and dried under a stream of nitrogen toafford product as a colorless solid (318 mg, 96%). ¹H NMR (CDCl₃)1.43-1.57 (m, 2 H), 1.77-1.79 (m, 6 H), 3.02-3.15 (m, 2 H), 3.27 (br s,2 H), 3.51 (br s, 1 H), 3.74 (s, 3 H), 3.77-3.89 (m, 2 H), 4.57-4.59 (m,1 H), 6.24-6.31 (m, 2 H), 6.55 (br s, OH), 6.67 (d, J=8.6, 1 H)7.18-7.27(m, 5 H). LC/MS 5.34 min, [M+1]⁺ 425.

Example 60 Preparation of Compound 108,4-[(1-((S)-3-benzyl-4-piperazin-1-yl)-aceticacid)]-7-methoxy-spiro[benzofuran-2(3 H), 1′-cyclopentane]

Prepared by the methods outlined for Examples 57/59 using compound 80(Example 32) as the amine coupling component. Oil and tan solid (65 and98%). LC/MS 5.65 and 5.29 min, [M+1]⁺ 452 and 437.

Example 61 Preparation of Compound 109,[(S)-2-Benzyl-4-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-piperazin-1-yl]-aceticacid

Prepared by the methods outlined for Examples 57/59 using6-((S)-3-Benzyl-piperazin-1-yl)-1-cyclopentyl-3-ethyl-1H-indazole(Example 35) as the amine coupling component. Oil and tan solid (77 and94%). LC/MS 6.37 and 5.65 min, [M+1]⁺ 462 and 447.

Example 62 Preparation of Compound 110,2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-N-methyl-acetamide

A solution of[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-aceticacid (Example 59) (21.2 mg, 0.05 mmol) in CH₂Cl₂ (0.5 mL) at 0° C. wastreated with DMAP (˜1 mg) and DCC (11.3 mg, 0.055 mmol) followed 5 minlater by a 2 M THF solution of methylamine (30 μL, 0.06 mmol). Thereaction mixture was stirred for 16 h, evaporated, and purified bysilica gel flash chromatography with 50% EtOAc/hexane, then 100% EtOAc,then 5% Me0H/Et0Ac as eluant to afford product as an oil (6.4 mg, 29%).LC/MS 5.09 min, [M+1]⁺ 438.

Example 63 Preparation of Compound 111,[(S)-2-Benzyl-4-(3-Cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-aceticacid hydrazide

Prepared by the method outlined for Example 62 using hydrazine hydrateas the amine component. Oil (51%). LC/MS 4.84 min, [M+1]⁺ 439.

Example 64 Preparation of Compound 112,[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-aceticacid N′-methyl-hydrazide

Prepared by the method outlined for Example 62 using methylhydrazine asthe amine component. Oil (73%). LC/MS 4.90 min, [M+1]⁺ 453.

Example 65 Preparation of Compound 113,[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-aceticacid N′,N′-dimethyl-hydrazide

Prepared by the method outlined for Example 62 usingunsym-dimethylhydrazine as the amine component. Oil (54%). LC/MS 5.04min, [M+1]⁺ 467.

Example 66 Preparation of Compound 114,2-1-(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-N-methoxy-acetamide

Prepared by the method outlined for Example 62 usingO-methylhydroxylamine hydrochloride (with 1 equivalent of triethylamineto neutralize hydrochloride salt) as the amine component. Oil (57%).LC/MS 5.28 min, [M+1]⁺ 454.

Example 67 Preparation of Compound 115, 2-[(S)-2Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-N-ethoxy-acetamide

Prepared by the method outlined for Example 62 usingO-ethylhydroxylamine hydrochloride (with 1 equivalent of triethylamineto neutralize hydrochloride salt) as the amine component. Oil (72%).LC/MS 5.30 min, [M+1]⁺ 468.

Example 68 Preparation of Compound 116, 2-[(S)-2Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-N-isobutoxy-acetamide

Prepared by the method outlined for Example 62 usingO-isobutylhydroxylamine hydrochloride (with 1 equivalent oftriethylamine to neutralize hydrochloride salt) as the amine component.Oil (67%). LC/MS 5.78 min, [M+1]⁺ 496.

Example 69 Preparation of Compound 117,2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-N-phenoxy-acetamide

Prepared by the method outlined for Example 62 usingO-phenylhydroxylamine hydrochloride (with 1 equivalent of triethylamineto neutralize hydrochloride salt) as the amine component. Oil (66%).LC/MS 6.13 min, [M+1]⁺ 516.

Example 70 Preparation of Compound 118,N-Allyloxy-2-[(S)-2-benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-acetamide

Prepared by the method outlined for Example 62 usingO-allylhydroxylamine hydrochloride (with 1 equivalent of triethylamineto neutralize hydrochloride salt) as the amine component. Oil (71%).LC/MS 5.46 min, [M+1]⁺ 480.

Example 71 Preparation of Compound 119,2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-N-benzyloxy-acetamide

Prepared by the method outlined for Example 62 usingO-benzylhydroxylamine hydrochloride (with 1 equivalent of triethylamineto neutralize hydrochloride salt) as the amine component. Oil (72%).LC/MS 5.90 min, [M+1]⁺ 530.

Example 72 Preparation of Compound 120,2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-N-hydroxy-acetamide

A solution of2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-N-benzyloxy-acetamide(Example 71) (30 mg, 0.0566 mmol)was dissolved in MeOH (10 mL), purgedwith a stream of nitrogen, treated with 20% Pd/C (100 mg, 50% watercontent), and hydrogenated under 40 psi pressure of hydrogen for 4 h.The crude reaction mixture was then purged with nitrogen, filtered, andevaporated. The crude product was then dissolved in chloroform (5 mL)and filtered through a nylon syringe filter to remove residual Pd/C. Theorganic solution was evaporated to afford product as a colorless foam(14 mg,. 56%). LC/MS 5.03 min, [M+1]⁺ 440.

Example 73

The following illustrate representative pharmaceutical dosage forms,containing a compound of formula I (‘Compound X’), for therapeutic orprophylactic use in humans.

(i) Tablet 1 mg/tablet Compound X = 100.0 Lactose 77.5 Povidone 15.0Croscarmellose sodium 12.0 Microcrystalline cellulose 92.5 Magnesiumstearate 3.0 300.0 (ii) Tablet 2 mg/tablet Compound X = 20.0Microcrystalline cellulose 410.0 Starch 50.0 Sodium starch glycolate15.0 Magnesium stearate 5.0 500.0 (iii) Capsule mg/capsule Compound X- =10.0 Colloidal silicon dioxide 1.5 Lactose 465.5 Pregelatinized starch120.0 Magnesium stearate 3.0 600.0 (iv) Injection 1 (1 mg/ml) mg/mlCompound X = (free acid form) 1.0 Dibasic sodium phosphate 12.0Monobasic sodium phosphate 0.7 Sodium chloride 4.5 1.0N Sodium hydroxidesolution q.s. (pH adjustment to 7.0-7.5) Water for injection q.s. ad 1mL (v) Injection 2 (10 mg/ml) ing/ml Compound X. (free acid form) 10.0Monobasic sodium phosphate 0.3 Dibasic sodium phosphate 1.1 Polyethyleneglycol 400 200.0 01N Sodium hydroxide solution q.s. (pH adjustment to7.0-7.5) Water for injection q.s. ad 1 mL (vi) Aerosol mg/can CompoundX. 20.0 Oleic acid 10.0 Trichloromonofluoromethane 5,000.0Dichlorodifluoromethane 10,000.0 Dichlorotetrafluoroethane 5,000.0

The above formulations may be obtained by conventional procedures wellknown in the pharmaceutical art.

All publications, patents, and patent documents are incorporated byreference herein, as though individually incorporated by reference. Theinvention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

What is claimed is:
 1. A compound of formula I:

wherein: R₁ is H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkanoyl,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkanoyloxy, (C₃-C₈)cycloalkyl,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, aryl, aryl(C₁-C₆)alkyl,aryl(C₁-C₆)alkoxy, aryl(C₁-C₆)alkanoyl, het, het(C₁-C₆)alkyl,het(C₁-C₆)alkoxy, or het(C₁-C₆)alkanoyl; n is 1; m is 1; W is O, S, ortwo hydrogens; X is N—Y—R₄; Y is a direct bond, —CH₂—, —C(═O)—, —C(═S)—,—O—, —C(═O)O—, —OC(═O), —C(═O)NR_(a), —S—, —S(═O)—, —S(═O)₂—, or—S(═O)₂NR_(a)—; R₄ is H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkanoyl,hydroxy, (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl,halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl, carboxy,aryl, aryl(C₁-C₆)alkyl, het, NR_(d)R_(e), —C(═O)NR_(d)R_(e),NR_(d)R_(e)(C₁-C₆)alkyl, or het(C₁-C₆)alkyl; R_(a) is H, (C₁-C₆)alkyl,(C₃-C₈)cycloalkyl, (C₁-C₆)alkoxy, (C₂-C₆)alkyl, or(C₃-C₈)cycloalkyl(C₁-C₆)alkyl; Z is a phenyl ring substituted with oneor more substituents independently selected from (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, (C₃-C₈)cycloalkyloxy, and(C₃-C₈)cycloalkyl(C₁-C₆)alkoxy; or Z is a phenyl ring that is fused to asaturated, partially unsaturated, or aromatic, mono- or bicyclic ringsystem comprising from about 3 to about 8 atoms selected from carbon,oxygen, and NR_(b), wherein the mono- or bicyclic ring system of Z isoptionally substituted with one or more R_(c), and wherein the phenylring that is fused to the mono- or bicyclic ring system is optionallysubstituted with one or more substituents independently selected from(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo(C₂-C₆)alkoxy,(C₃-C₈)cycloalkyloxy, and (C₃-C₈)cycloalkyl(C₁-C₆)alkoxy; R_(b) isabsent, H, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, (C₁-C₆)alkoxy(C₂-C₆)alkyl,or (C₃-C₈)cycloalkyl(C₁-C₆)alkyl; R_(c) is (C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₁-C₆)alkanoyl, (C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkanoyloxy,(C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, halo(C₁-C₆)alkyl,aryl, aryl(C₁-C₆)alkyl, aryl(C₁-C₆)alkoxy, aryl(C₁-C₆)alkanoyl, het,het(C₁-C₆)alkyl, het(C₁-C₆)alkoxy, or het(C₁-C₆)alkanoyl; each R_(d) andR_(e) is independently H, hydroxy, (C₁-C₆)alkyl, amino,amino(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy,(C₂-C₆)alkenyloxy, (C₂-C₆)alkynyloxy, (C₁-C₆)alkanoyl,(C₁-C₆)alkoxycarbonyl, (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl,aryl, aryl(C₁-C₆)alkyl, NR_(f)R_(g), or aryl(C₁-C₆)alkoxy; and eachR_(f) and R_(g) is independently H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₁-C₆)alkanoyl, (C₁-C₆)alkoxycarbonyl, (C₃-C₈)cycloalkyl,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, aryl, aryl(C₁-C₆)alkyl, oraryl(C₁-C₆)alkoxy; or R_(f) and R_(g) together with the nitrogen towhich they are attached form a pyrrolidino, piperidino, piperazino,morpholino, or thiomorpholino ring; wherein any aryl or het of R₁ or R₄is optionally substituted with one or more substitutents independentlyselected from (C₁-C₆)alkyl, phenyl, (C₁-C₆)alkoxy, (C₁-C₆)alkanoyl,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkanoyloxy, (C₃-C₈)cycloalkyl,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₃-C₈)cycloalkyloxy,(C₃-C₈)cycloalkyl(C₁-C₆)alkoxy, halo(C₂-C₆)alkoxy, cyano, nitro, halo,carboxy or NR_(d)R_(e); and wherein the ring containing X is optionallysubstituted on carbon with one or more halo, (C₁-C₆)alkyl, or(C₁-C₆)alkoxy; and when R₁ is H or C₁ alkyl, —Y—R₄ is not aryl(C₁-C₆)alkyl or hydroxy(C₁-C₆)alkyl; and when R₁ is H and —Y—R₄ is H, Z is nota phenyl ring substituted with only one halo(C₁-C₆)alkyl or only onehalo(C₁-C₆)alkoxy substituent; or a pharmaceutically acceptable saltthereof.
 2. The compound of claim 1 wherein R₁ is (C₁-C₆)alkoxy,(C₁-C₆)alkanoyl, (C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkanoyloxy,(C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, halo(C₁-C₆)alkyl,aryl, aryl(C₁-C₆)alkyl, aryl(C₁-C₆)alkoxy, aryl(C₁-C₆)alkanoyl, het,het(C₁-C₆)alkyl, het(C₁-C₆)alkoxy, or het(C₁-C₆)alkanoyl.
 3. Thecompound of claim 1 wherein R₁ is H, (C₁-C₆)alkyl, aryl,aryl(C₁-C₆)alkyl, or het.
 4. The compound of claim 1 wherein R₁ is H,benzyl, indolyl, phenyl, 2-methylpropyl, 2-methylbenzyl, 3-methylbenzyl,4-methylbenzyl, α-phenylbenzyl, phenethyl, 1-naphthylmethyl,2-naphthylmethyl, 4-phenylbenzyl, 4-ethoxybenzyl, isopropyl,cyclohexylmethyl, 2-methoxyphenyl, 3-methoxyphenyl, or 4-methoxyphenyl.5. The compound of claim 1 wherein Y is a direct bond, —CH₂—, —C(═O)—,or —S(═O)₂—.
 6. The compound of claim 1 wherein R₄ is H, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, (C₁-C₆)alkanoyl, hydroxy(C₂-C₆)alkyl,(C₁-C₆)alkoxycarbonyl, carboxy, aryl, aryl(C₁-C₆)alkyl, het,NR_(d)R_(e), —C(═O)NR_(d)R_(e), NR_(d)R_(e)(C₁-C₆)alkyl, orhet(C₁-C₆)alkyl.
 7. The compound of claim 1 wherein Y—R₄ is H,tert-butoxycarbonyl, formylmethyl, pyridylmethyl, methyl,ethylaminocarbonyl, ethylsulfonyl, benzylsulfonyl, benzyl, acetyl,methoxycarbonylmethyl, methylsulfonyl, ethyl, carboxymethyl, propyl,2-hydroxyethyl, methoxyaminocarbonylmethyl,benzyloxyaminocarbonylmethyl, prop-2-eneyloxyaminocarbonylmethyl,hydroxyaminocarbonylmethyl, hydroxyacetyl,2-methylhydrazocarbonylmethyl, hydrazocarbonylmethyl,2,2-dimethylhydrazo-carbonylmethyl, or ethoxycarbonyl.
 8. The compoundof claim 1 wherein Z is a phenyl ring substituted with one or moresubstituents independently selected from (C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy, (C₃-C₈)cycloalkoxy, and(C₃-C₈)cycloalkyl(C₁-C₆)alkoxy.
 9. The compound of claim 1 wherein Z isa phenyl ring that is fused to a saturated, partially unsaturated, oraromatic, mono- or bicyclic ring system comprising from about 3 to about8 atoms selected from carbon, oxygen, and NRb, wherein the mono- orbicyclic ring system of Z is optionally substituted with one or more Rc,and wherein the phenyl ring that is fused is fused to the mono- orbicyclic ring system is optionally substituted with one or moresubstituents independently selected from (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,(C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, (C₁-C₆)alkoxy,halo(C₂-C₆)alkoxy, (C₃-C₈)cycloalkyloxy, and(C₃-C₈)cycloalkyl(C₁-C₆)alkoxy.
 10. The compound of claim 1 wherein Zhas the following formula:

wherein R₂ is (C₁-C₆)alkyl, or halo(C₁-C₆)alkyl; and R₃ is (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, or (C₃-C₈)cycloalkyl(C₁-C₆)alkyl.11. The compound of claim 10 wherein R₂ is methyl and R₃ is cyclopentyl.12. The compound of claim 1 wherein Z is selected from a structure offormula III, IV, and V:

that is optionally substituted with one or more substituents selectedfrom (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo(C₂-C₆)alkoxy,(C₃-C₈)cycloalkyloxy, and (C₃-C₈)cycloalkyl(C₁-C₆)alkoxy; wherein p is1, 2, 3, 4, 5, or
 6. 13. The compound of claim 1 wherein Z is selectedfrom a structure of formula VI, VII, and VIII:

wherein: R_(j), R_(k), R_(m), R_(n), and R_(p) are each independentlyselected from H, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo(C₂-C₆)alkoxy,(C₃-C₈)cycloalkyloxy, and (C₃-C₈)cycloalkyl(C₁-C₆)alkoxy; and p is 1, 2,3, 4, 5, or
 6. 14. The compound of claim 13 wherein R_(j), and R_(k) areeach independently selected from H and methyl; R_(m) is methoxy; R_(n)is cyclopentyl; R_(p) is ethyl; and p is
 3. 15. The compound of claim 1which is:(S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-(2-methyl-benzyl)-piperazine;(S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-(3-methyl-benzyl)-piperazine;(S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-(4-methyl-benzyl)-piperazine;(S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-(2-methoxy-benzyl)-piperazine;(S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-(3-methoxy-benzyl)-piperazine;(S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-(4-methoxy-benzyl)-piperazine;(S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-(4-ethoxy-benzyl)-piperazine;(S)-3-Biphenyl-4-ylmethyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine;(S)-3-Benzhydryl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine;(S)-3-Cyclohexylmethyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine;3-[(S)-4-(3-Cyclopentyloxy-4-methoxy-phenyl)-piperazin-2-ylmethyl]-1H-indole;4-[(S)-3-benzyl-1-piperzinyl]-7-methoxy-spiro[benzofuran-2(3H),1′-cyclopentane];6-((S)-3-Benzyl-piperazin-1-yl)-1-cyclopentyl-3-methyl-1H-indazole;1-Cyclopentyl-3-ethyl-6-piperazin-1-yl-1H-indazole;6-((S)-3-Benzyl-piperazin-1-yl)-1-cyclopentyl-3-ethyl-1H-indazole;(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-1-pyridin-2-ylmethyl-piperazine;(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-1-pyridin-3-ylmethyl-piperazine;(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-1-pyridin-4-ylmethyl-piperazine;(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-1-(3H-imidazol-4-ylmethyl)-piperazine;(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-1-(1H-imidazol-2-ylmethyl)-piperazine;(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-1-methanesulfonyl-piperazine;(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-1-ethanesulfonyl-piperazine;(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-1-benzylsulfonyl-piperazine;(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine-1-carboxylicacid ethylamide; 1-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-2-hydroxy-ethanone;2-Amino-1-[(S)-2-benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-ethanone,hydrochloride salt;1-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-2-methylamino-ethanone,hydrochloride salt;4-[(1((S)-3-benzyl-4-piperazin-1-yl)-2-hydroxy-ethanone)]-7-methoxy-spiro[benzofuran-2(3H),1′-cyclopentane];1-[(S)-2-Benzyl-4-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-piperazin-1-yl]-2-hydroxy-ethanone;2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-acetamide;2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-ethanol;4-[(1((S)-3-benzyl-4-piperazin-1-yl)-aceticacid)]-7-methoxy-spiro[benzofuran-2(3H), 1′-cyclopentane];[(S)-2-Benzyl-4-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-piperazin-1-yl]-aceticacid;2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-N-methyl-acetamide;[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-aceticacid hydrazide;[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-aceticacid N′-methyl-hydrazide;[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-aceticacid N′,N′-dimethyl-hydrazide;2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-N-methoxy-acetamide;2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-N-ethoxy-acetamide;2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-N-isobutoxy-acetamide;2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-N-phenoxy-acetamide;N-Allyloxy-2-[(S)-2-benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-acetamide;2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-N-benzyloxy-acetamide;or2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-N-hydroxy-acetamide.16. The compound of claim 1 which is:1-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-2-hydroxy-ethanone;2-Amino-1-[(S)-2-benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-ethanone,hydrochloride salt;2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-ethanol;4-[(1((S)-3-benzyl-4-piperazin-1-yl)-aceticacid)]-7-methoxy-spiro[benzofuran-2(3H), 1′-cyclopentane];[(S)-2-Benzyl-4-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-piperazin-1-yl]-aceticacid;2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-acetamide;2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-N-methyl-acetamide;2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-N-hydroxy-acetamide;N-Allyloxy-2-[(S)-2-benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-acetamide;2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-N-benzyloxy-acetamide;[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-aceticacid hydrazide;[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-aceticacid N′-methyl-hydrazide; or[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-aceticacid N′,N′-dimethyl-hydrazide; or a pharmaceutically acceptable saltthereof.
 17. A pharmaceutical composition comprising a compound of claim1, in combination with a pharmaceutically acceptable diluent or carrier.